June 9-13, 2017; San Diego, CA; Full Report – Draft

Executive Highlights

In this report, we provide our full coverage of the 77^th Scientific Sessions of the American Diabetes Association (ADA), held at the San Diego Convention Center from June 9-13, 2017. The meeting drew more than 16,000 attendees, including nearly 13,000 healthcare or scientific professionals. Notably, a majority of attendees – 55% – arrived from outside of the US. The meeting is becoming more and more international, and the proportion of international participants has hovered around 50%-60% since 2012. The overall attendance number is comparable to last year’s attendance at the 76^th Scientific Sessions held at in New Orleans, though the number of professionals is down (12,736 this year, compared to 13,265 last year). 99 symposia and over 2,500 original research presentations were featured over the course of the five-day meeting, including oral presentations in 49 dedicated sessions and 2,150 poster presentations, reflecting the sheer quantity of research work currently dedicated to diabetes and obesity. For comparison, both the total number of symposia and the number or posters is up from last year’s ADA (which featured 95 symposia and 2,026 posters).

Major diabetes therapy highlights at this ADA included not one but two cardiovascular outcome trial (CVOT) presentations. The CANVAS trial of J&J’s SGLT-2 inhibitor Invokana (canagliflozin) demonstrated striking cardiovascular and renal benefits, and as observed in the EMPA-REG OUTCOME trial for Lilly/BI’s Jardiance (empagliflozin), was shown to be cardioprotective, a win for the class. The story was complicated by worrisome safety results, particularly a nearly doubled increased risk for lower-extremity amputation with Invokana –low in number but the same risk across all patients (all of whom had a lot of complications so we don’t view this as generalizable among the diabetes population – but it does seem to be among all risk cohorts in CANVAS). This story is still unfolding. As expected, the DEVOTE trial demonstrated CV safety for Novo Nordisk’s next-generation Tresiba (insulin degludec), but the real headliner here was the 40% reduction in severe hypoglycemia and 53% reduction in nocturnal severe hypoglycemia associated with Tresiba compared to standard of care Lantus (insulin glargine). These are fantastic results that are immediately useful for patients, assuming this goes on label – we were impressed to see the results submitted almost immediately after the presentation. All in all, outcomes beyond A1c was a major focus across diabetes therapy data presentation at ADA, from trials evaluating the CV or renal impact of diabetes drugs or combinations to hypoglycemia and weight loss data to patient-reported outcomes. We also saw quite a bit of forward momentum in adjunct therapies for type 1 diabetes (though the cures and prevention findings were more disappointing), and innovation in rapid-acting insulins and more patient- and caregiver-friendly glucagon products for hypoglycemia.

In diabetes technology, this ADA was more about products and partnerships than major new data. We were elated to see: meaningful progress on CGM outcomes standardization; a more commercial feel in the automated insulin delivery field (Medtronic MiniMed 670G, Tandem PLGS, Insulet Horizon, Diabeloop); a quickly-expanding pipeline of insulin dose titration and dose capture products (Common Sensing, Bigfoot/Timesulin, Sanofi, Hygieia, Amalgam Rx, Voluntis); a strong reminder of how connected devices can drive real-world data collection and more insightful products (Abbott FreeStyle Libre, Sugar.IQ); plenty of commentary on expanding CGM to type 2 diabetes; and scores of posters on remote coaching and digital platforms. There’s no question about it – this field is moving faster from a higher base relative to a year ago. The big questions are where the successes are, whether these products can scale, reach the patients most in need, truly save HCPs hassle, and take cost out of the system … we are more optimistic than we were a year ago and aware that it’s all taken longer than expected.

Additionally, this year’s ADA meeting featured a growing focus on diabetes-adjacent therapies, an increased spotlight on prevention, and a dedicated effort to highlight psychosocial care in diabetes, a first at ADA. We were also extremely impressed by the annual ADA Pathway to Stop Diabetes symposium and the several award lectures we attended. And while not part of the official program, the Monday night learning and socializing kept going (and going and going) with a record-breaking three events from The diaTribe Foundation: the TCOYD-partnered 11^th annual Diabetes Forum, the 2^nd annual Musings Under the Moon, and the inaugural Musings After Hours.

In this report, we include 26 themes immediately below, followed by detailed discussion and commentary from 355 talks and discussions (orals, symposia, lectures, panels, corporate symposia, and product theaters), 100 posters, and 25 exhibits. All in all, our full report is nearly 500 pages long and contains nearly 250,000 words. Our team is bringing you more insights than ever before this year, with our full report growing from our ADA 2016 coverage of 319 talks, 60 posters, and 28 exhibits.

Below, we have organized our writing into 19 specialized reports:

Diabetes Therapy:

(1) SGLT-2 Inhibitors: 21 talks and 9 posters, up from 19 talks and 9 posters in 2016

(2) Insulin Therapy: 24 talks and 17 posters, up from 20 talks and 6 posters in 2016

(3) GLP-1 Agonists: 20 talks and 10 posters, compared to 22 talks and 8 posters in 2016

(4) DPP-4 Inhibitors: 4 talks and 2 posters, down from 6 talks and 9 posters in 2016

(5) Novel Therapies: 11 talks and 13 posters, up from 12 talks and 7 posters in 2016

(6) Type 1 Diabetes Cures, Adjunct Therapies and Pathophysiology: 37 talks and 3 posters, up from 19 talks in 2016

Diabetes Technology:

(7) Closing the Loop and Insulin Delivery: 29 talks and 10 posters, down slightly from 29 talks and 7 posters in 2016

(8) Glucose Monitoring: 17 talks and 14 posters, up from 20 talks and 7 posters in 2016

(9) Digital Health: 23 talks and 11 posters, up from 14 talks and 2 posters in 2016

Additional Highlights of Critical Interest:

(10) Obesity and Prediabetes Care: 24 talks and 3 posters, down from 40 talks and 2 posters in 2016

(11) Diabetes Complications: 31 talks and 1 poster, up from 24 talks in 2016

(12) Treatment Algorithms and Strategies: 35 talks, up from 18 talks and 1 poster in 2016

(13) Policy and Reimbursement: 10 talks and 5 posters, down from 29 talks in 2016

(14) Epidemiology, Education, and Additional Topics: 54 talks and 2 posters, up from 32 talks and 1 poster in 2016

(15) Generic Drugs: 10 talks, down from 11 talks and 1 poster in 2016

(16) Exhibit Hall: 5 talks and 25 exhibits, down from 4 talks and 28 exhibits in 2016

Events:

(17) TCOYD/The diaTribe Foundation Forum

(18) Musings Under the Moon

(19) Musings After Hours

We’ve highlighted in yellow any presentations and commentary that we found particularly notable. Talks that were either not published in our daily highlights reports or have been significantly expanded are highlighted in blue (unless that talk was a notable yellow highlight).

When applicable, certain talks and sessions have been duplicated in multiple chapters (e.g., content on GLP-1/basal insulin products may appear in both the GLP-1 Agonist and Insulin Therapy categories).

We send along our most sincere appreciation to all our Closer Look readers for their brilliance, support, concern, enthusiasm, encouragement, and incredibly hard work day in and day out. We watch you and we are so incredibly moved and grateful for what you do for diabetes and obesity. A special shoutout from Kelly and John to Adam Brown, Helen Gao, and all the Close Concerns associates, alums, friends of the company who added so much to this ADA Scientific Sessions gathering – and whom we owe the world to make so much learning happen for us all. Notably, today is Helen’s LAST day before moving on to medical school at Northwestern (and this is her last hour!). How very lucky we have been to work with her and to be part of her leadership presence and to see all that she made happen to bring the science home to you. What an incredible healthcare leader she will be (you can even see her again in November, when she is for the second year on faculty at The World Congress on Clinical Trials in Diabetes; she’ll be speaking on public perceptions on clinical trials in diabetes and will bring a medical school perspective). We know those of you who saw Adam at ADA were so lucky – I hear that 10,000 people now have his amazing new book Bright Spots and Landmines in their hands! What a powerhouse job he did leading everyone through technology and digital health.  On another exciting note, we welcome new associates Ann Carracher and Maeve Serino to Close Concerns, who graduated from Dartmouth and Williams just one and three days before starting their first days at Close Concerns (Ann in the midst of ADA!). More than 300 college seniors applied this year to associate roles at Close Concerns, The diaTribe Foundation, and dQ&A – yet again, we’re so lucky that the most talented college seniors chose us and entrusted us with this time in our associate programs. AND! Our first year dream team class of Abigail Dove, Brian Levine, and Payal Marathe graduate today to second year associates – please send a virtual cheers to them. We’ve had our incredible associate program over a decade now, and I’m so indebted to every single one who has joined for taking this journey with me, for trusting John and me, and for making this fantastic learning happen for all of you. Thank you to them, for this. Happy weekend! 

Themes

Diabetes Therapy

CANVAS CVOT for Invokana: Affirmation of SGLT-2 Inhibitor CV and Renal Benefit, but Complicated Safety Story

• First, the good news – the CANVAS program demonstrated the cardiovascular superiority of Invokana (canagliflozin), as measured by the primary endpoint of three-point MACE (non-fatal MI, non-fatal stroke, and CV death). In the program, canagliflozin therapy reduced risk of MACE events by 14% (95% CI:0.75-0.97, p=0.0158 for superiority). Further, canagliflozin therapy produced an extremely impressive benefit for a secondary endpoint of hospitalization for heart failure, reducing risk by 33% (95% CI:0.52-0.87). As the second SGLT-2 inhibitor to report CV results – following the highly unexpected and impressive EMPA-REG OUTCOME findings demonstrating a CV benefit for Lilly/BI’s Jardiance (empagliflozin) – it’s perhaps only natural that many in the field are already drawing direct comparisons between the two trials, even though we stress they are not directly comparable for a number of reasons outlined below. Indeed, however, the CANVAS investigators themselves directly compared the hazard ratios and confidence intervals of a number of key endpoints across CANVAS and EMPA-REG OUTCOME – see the Dr. David Matthews “Implications for Clinical Practice” section below for more on this.
  
  • Several key differences in both the participant population and CV findings exist between the CANVAS and EMPA-REG OUTCOME trials. In terms of participant population, EMPA-REG OUTCOME exclusively enrolled those with a prior history of CV disease – thus, the generalizability of the results to a lower-risk patient population has been a major question in the 21 months since EMPA-REG OUTCOME was presented at EASD 2015. On the other hand, CANVAS sheds some light on this question – about one-third of participants enrolled in the trial had risk factors for cardiovascular disease but no established history, thus creating a primary prevention cohort. There was no heterogeneity of benefit (p-value for interaction was non-significant) between the primary prevention and secondary prevention cohort in the trial (see Dr. Bruce Neal’s presentation of the Effects on Cardiovascular Outcomes below for more detail on this). Thus, there’s some early suggestion of CV benefit for SGLT-2 inhibitors even in a primary prevention cohort – we expect the DECLARE CVOT for AZ’s Farxiga, with its 17,000+ participant population, will offer additional information on this front when it reports in 2019.
  • In terms of CV endpoints, CANVAS did not demonstrate a CV or all-cause mortality benefit for canagliflozin. While the point estimate for the hazard ratio of both findings was in the “right direction,” the confidence intervals crossed the line of unity and just missed statistical significance. For all-cause mortality, the hazard ratio was 0.87 (95% CI:0.74-1.01, p=0.24) – this was particularly disappointing since this was the second endpoint in the pre-specified hierarchical testing structure and thus the other endpoint results in the study can only be considered exploratory. For CV death, the hazard ratio was 0.87 (95% CI: 0.72-1.06). This contrasts with the strong 38% risk reduction for CV death (p<0.0001) and 32% risk reduction for all-cause death (p<0.001) in the EMPA-REG OUTCOME trial. It’s unclear what kind of label indication the CANVAS findings will be able to support, given that Jardiance is only indicated for CV death rather than for its primary MACE finding (in fact, some on the FDA Advisory Committee felt that the p-value for the primary endpoint in EMPA-REG OUTCOME may not be convincing enough – though the p-value for superiority in CANVAS is more compelling). On the plus side, canagliflozin did not demonstrate a signal for increased stroke as empagliflozin did – in fact, the point estimate for stroke and all other components of expanded MACE (including hospitalization for unstable angina) were on the right side of unity, a reassuring finding indeed.
• All in all, the CV findings of the CANVAS program offer further reassurance of the “validity” of the EMPA-REG OUTCOME benefit and suggest that the CV benefit, at least, is a class effect for SGLT-2 inhibitors. Given the highly unexpected and unprecedented nature of EMPA-REG OUTCOME, the question of class effect has been one of THE most frequently asked questions regarding SGLT-2 inhibitors and CV benefit over the last two years. The other most popular question is “what is the mechanism of benefit?” A non-inferiority CV finding in CANVAS would have potentially thrown into question the validity of the EMPA-REG OUTCOME benefit and may have led some to suggest the benefit demonstrated in the trial was a statistical fluke. Indeed, many key thought leaders – who often make up diabetes guidelines committees – have expressed the desire for more data from other agents in the class before wholeheartedly recommending SGLT-2 inhibitors (or even just empagliflozin) as a preferred therapy for those with a history of cardiovascular disease. With two positive CVOTs for the SGLT-2 inhibitor class, we imagine we might see more enthusiastic recommendations for the class for CV benefit in future guidelines. Thus far, the ADA 2017 Standards of Care recommend only the consideration of empagliflozin (and GLP-1 liraglutide) in those with established CV disease and the AACE guidelines have not yet changed recommendations based on CVOT data. On balance, the overall CANVAS findings appear at this stage to be more positive for Jardiance than for Invokana. We expect this further confirmation of CV benefit will boost the SGLT-2 inhibitor class as a whole and we expect Jardiance in particular will benefit, given its compelling CV benefit (and indication), as well as the lack of worrisome and unexpected safety signals in the trial (more on this below). Indeed, Invokana has already been losing market share largely to Jardiance (while Farxiga share has been relatively sustained) for several quarters now, and we expect this trend may continue in future quarters – this is not at all unexpected given that all “first to market” compounds do lose share. We do believe the unexplained amputation outcome, in particular, will be a focus of manufacturers, and we hope that Janssen is able to share more data on this front. Overall, while it’s too early to say definitively how patients and providers will react to these results, we expect the messaging from all three SGLT-2 inhibitor manufacturers to be positive on CV and mixed on amputation and fractures (we believe there is also more to be known about these risks for other manufactures).
• The more negative headline from CANVAS/CANVAS-R is the near doubling of lower-extremity amputation risk with canagliflozin vs. placebo (HR=1.97, 95% CI: 1.41-2.75, P<0.001). Although it is a low absolute risk overall (many fewer amputations take place than heart disease annually for people with diabetes), the risk appeared to occur across all patients, not just those who had previous amputations. That said, all patients in the study had a high degree of elevated risk, as two-thirds of participants had a previous history of a CV events and one-third of participants had at least two cardiovascular risk factors. There were 187 lower limb amputations across these two outcomes trials, occurring at a rate of 6.3/1,000 patient-years in the canagliflozin arm vs. 3.4/1,000 patient-years in the placebo arm. Approximately 71% of these amputations occurred at the level of the toes or forefoot, though some were above the ankle and a smaller number were above the knee. This leads to a murky risk/benefit profile for Invokana on the face of it though there are a number of confounders. On the negative side, Dr. David Matthews shared, for every 1,000 patients treated with canagliflozin over five years, we can expect 23 fewer MACE events, 17 fewer hospitalizations for heart failure, 16 fewer renal composite endpoints (renal death, renal replacement therapy, or 40% reduction in eGFR), and 15 additional lower limb amputations – 10 at the level of toe/forefoot, five above the ankle. What makes this even more challenging is that canagliflozin doubled amputation risk across all risk factors, including prior amputation and baseline peripheral vascular disease. Without any insight into what is mediating canagliflozin’s adverse impact on the lower limbs, the risk seems more likely to be associated with the molecule itself although this hasn’t been established and there are a number of points related to things like adjudication that aren’t discussed broadly but may have had a real impact. We look forward to seeing “real world data” like the data around pancreatitis and GLP-1 a few years ago. In the meantime, HCPs won’t at this stage be able to tailor prescriptions based on patient disposition; that is to say, if the effect on lower limb amputations was driven by a particular subgroup, such as participants with baseline peripheral vascular disease, this safety issue might be circumvented with a single black box warning not to prescribe Invokana to patients with peripheral vascular disease.
  
  • As a reminder, this trial included a very broad set of patients. In total, over 10,000 patients were enrolled and, notably, the CANVAS program enrolled both those with established cardiovascular disease at baseline (a secondary prevention cohort) and those with two or more CV risk factors but no history of cardiovascular disease (a primary prevention cohort). This contrasts with the EMPA-REG OUTCOME trial, which enrolled only patients with a history of cardiovascular disease at baseline.
  • We have very little information or insight at this stage as to how this will all play out in real-world prescribing habits and formulary negotiations. Dr. Dan Drucker foreshadowed a slow attrition away from Invokana, with new SGLT-2 starts favoring Lilly/BI’s Jardiance (with demonstrated cardioprotection and no associated amputation risk) or AZ’s Farxiga. On the other hand, Dr. Anne Peters suggested that some providers may keep patients on canagliflozin due to formulary requirements, or because of greater glucose-lowering and weight loss vs. empagliflozin (in her anecdotal clinical experience). While some have suggested a worst-case scenario of HCPs steering clear of SGLT-2 inhibitor products in general, once they learn of lower limb amputation risk, we doubt that will happen. While the EMPA-REG study group did not observe a similar increase in amputations in the EMPA-REG OUTCOME trial, that was a shorter trial with a more homogenous population.
  • While the heightened risk in CANVAS/CANVAS-R appeared fairly early on, at year one, the events were adjudicated very differently – with CANVAS/CANVAS-R prospectively and EMPA-REG retrospectively.
    • This reinforces yet again the need for more standardization on the global regulatory front. We expect to see manufacturers of SGLT-2 agents come together and invest in real-world data collection on this and other safety issues – we’d hate for lower-extremity amputations to define the narrative for this class, given the profound glycemic, CV, renal, and weight benefits and given the lack of standardized data from all trials.
  • This safety data from the CANVAS program also reminds us that strong education on foot care for people with diabetes is lacking. In fact, recent conversations have reinforced that this signal could shine a light on the importance of greater education on foot care for people with diabetes – we hope J&J and others will be a leader in expanding understanding/management of this complication. Currently, we don’t believe patients have much education at all about how to minimize this risk and in fact, perhaps key education could provide significantly more benefit. In general, messaging around this potential safety concern will be crucial not only for J&J, but for Lilly/BI around the Jardiance franchise and for AZ around the Farxiga franchise as well.
• The positive renal data was a key bright spot in the CANVAS results, and contributes to mounting evidence for a beneficial impact of SGLT-2 inhibitors in general on renal complications of diabetes. Canagliflozin showed impressive signs of renal protection, including a 27% risk reduction for progression to albuminuria and a 40% risk reduction for a renal composite outcome (encompassing renal death, renal replacement therapy, or 40% reduction in eGFR). This comes on the heels of positive renal outcomes in the EMPA-REG OUTCOME trial, where empagliflozin showed a 39% risk reduction (HR: 0.61; 95% CI: 0.53-0.70; p<0.001) for the trial’s main renal endpoint of incident or worsening nephropathy (progression to macroalbuminuria or doubling of serum creatinine accompanied by eGFR ≤45 ml/min/1.73 m² or renal replacement therapy or death due to renal disease). These results are truly profound given the currently enormous unmet need for new therapies to treat chronic kidney disease, and to this end all three of the main SGLT-2 inhibitors on the market are now being explicitly studied for renal outcomes – canagliflozin in the CREDENCE trial, dapagliflozin in the Dapa-CKD trial, and empagliflozin in a just-announced chronic kidney disease trial from Lilly/BI.

SGLT-2 Inhibitor Safety and the Risk/Benefit Profile

• The amputation data in CANVAS certainly complicates how patients, providers, and payers will conceive of the risk/benefit profile for SGLT-2 inhibitors. With any new therapy or drug class, it’s easy to get swept up in the prospect of superior glucose-lowering and added benefits, from weight loss, to blood pressure reductions, to cardio- and renal protection. Based on the outcomes data we have so far on SGLT-2 inhibitors (CANVAS for canagliflozin and EMPA-REG OUTCOME for empagliflozin), all of these advantages hold true, and warrant tremendous excitement. On the other hand, because these agents are relatively new, real-world evidence is still accruing and additional safety signals may come to light. Questions ensue regarding canagliflozin and lower-extremity amputation risk, and above all else, we wonder – how will various players in diabetes care interpret the risk/benefit trade-offs for Invokana and other SGLT-2 inhibitors, given that there are not yet head-to-head CVOTs (and we don’t anticipate these will emerge)? Opinions from diabetes thought leaders have been mixed. Some, including Dr. George King (Joslin Diabetes Center, Boston, MA), suggest that the CV and renal results should overshadow amputation-related concerns, especially since this risk could be managed by improving patient education on foot care (it’s also true that amputations are far less common that heart attacks and strokes). Others, including Dr. Daniel Drucker (Mount Sinai Hospital, Toronto, Canada) forecast a gradual attrition of Invokana sales, as new SGLT-2 starts will favor Jardiance (or Farxiga) going forward. This has already been happening to some extent, even before the release of the CANVAS results, as Invokana’s share of the SGLT-2 inhibitor market has been decreasing in recent quarters. In another scenario, while it’s possible that busy healthcare providers will stay clear of all SGLT-2 inhibitor products because of red flags raised, we doubt this will happen due to safety (the access is another issue), even given other controversies surrounding SGLT-2s (bone fracture, DKA, etc). Overall, the amputation risk must definitely be conveyed to clinicians and we hope the education is good for them and that consensus builds on how to approach it. Overall, CANVAS CV results corroborate EMPA-REG OUTCOME CV results and point to a very real cardioprotective benefit to these agents. As one of the biggest headlines of ADA 2017 – if not the biggest – CANVAS forces all players in the diabetes field to appreciate safety data from outcomes trials, and begs for a safety-focused analysis of real-world SGLT-2 inhibitor datasets. We’re expecting a lot of back-and-forth on the risk/benefit profile of Invokana and other SGLT-2 inhibitors in the year to come.

Devote CVOT for Tresiba: Hypoglycemia Benefit, Opportunities for Future Trials

• The big headliner from DEVOTE is the demonstrated superior reduction in severe and nocturnal severe hypoglycemia with Tresiba vs. Lantus in long-term, randomized, double-blinded, large outcomes trial. Tresiba was associated with a very significant 40% relative risk reduction in the overall rate of severe hypoglycemia compared to Lantus (HR=0.60, 95% CI 0.48-0.76, p<0.001 for superiority) and a whopping 53% reduced risk for nocturnal severe hypoglycemia (HR=0.47, 95% CI: 0.31-0.73, p<0.001). Overall, a participant taking Tresiba was 27% less likely to experience one or more episodes of severe hypoglycemia (HR=0.73, 95% CI:0.60-0.89, p<0.001). Very impressively, this reduction in hypoglycemia occurred in the context of non-inferior A1c and superior fasting plasma glucose reductions for Tresiba compared to Lantus. These results further substantiate the hypoglycemia reduction findings in the SWITCH 1 and SWITCH 2 trials - these trials also demonstrated impressive hypoglycemia risk reduction with Tresiba therapy compared to Lantus, though this was demonstrated in a much smaller and shorter blinded crossover study (in which participants served as their own controls). Data from multiple trials confirming risk reduction for hypoglycemia will likely prove convincing and compelling as patients, providers, and even payers consider the “validity” of benefit – we’re curious if we might even see these findings discussed in future iterations of diabetes treatment guidelines.
  
  • That said, there are several limitations to the findings from the current study. For example, only information on severe hypoglycemia was collected and adjudicated, so it’s difficult to assess the impact of Tresiba on “mild-to-moderate” hypoglycemia, though the SWITCH 2 trial showed a 30% reduction in overall symptomatic hypoglycemia. This does not affect “health outcomes” as much as severe hypoglycemia does, but this is still clearly an area of interest to clinicians and patients as it certainly affects adherence, productivity, etc. As we understand it, there was no systematic collection of blood glucose levels or to insulin titration or mandated laboratory fasting blood glucose; as a result, Novo Nordisk says it could not have assessed incidence of blood glucose under 70 mg/dl because it didn’t have the full dataset. It’s unclear what data on this front would show – we certainly hope Tresiba would reduce incidence of blood sugars ≤70 mg/dl, as “less-severe” levels of hypoglycemia still have enormous quality of life and engagement and adherence and productivity implications for patients. We very much hope that inclusion of such data will be considered going forward. Overall, we continue to believe that CGM studies would be enormously helpful in characterizing the benefit of next-generation insulin products especially (but other drugs as well) and we wish that CGM data could have been gathered for this large and long-term study. We recognize, of course, that this study initiated many years ago and CGM accuracy improved significantly with the advent of Dexcom’s G4 approved in 2012, just before the 2013 study start date for DEVOTE and well after the DEVOTE clinical trial design was finalized.
• With the DEVOTE results we can certainly rest assured that Tresiba is at the very least safe from a CV standpoint. Tresiba demonstrated non-inferiority compared to standard of care insulin glargine (Sanofi’s Lantus) for the primary 3-point MACE composite endpoint, as well as each of its individual components (non-fatal MI, non-fatal stroke, and CV death). Many of these hazard ratios trended in the “right direction” – more on this below – though we cannot draw any definitive conclusions about potential cardioprotective benefit. That said, non-inferiority in and of itself is reassuring given Tresiba’s long and complicated regulatory history. As a reminder, the product’s first regulatory submission in the US received a Complete Response Letter (CRL) from the FDA, requesting a CVOT to further investigate a signal for increase expanded MACE risk observed in the phase 3 trials. The FDA’s eventual approval based on firewalled interim data was certainly reassuring on this front and we’re pleased to get our hands on full CVOT data that suggests not even a whiff of increased risk for Tresiba.

Outcomes Beyond A1c: Cardiovascular, Renal, Hypoglycemia, Patient-Reported

• Outcomes beyond A1c were front and center in many clinical trial findings presented at ADA 2017. Each year at the Scientific Sessions, the ADA selects a number of particularly high-profile clinical trial results to highlight in dedicated symposia sessions, rather than in oral presentations. Of the six such dedicated symposia highlighted on the ADA 2017 meeting webpage, five were focused on trials investigating cardiovascular endpoints in diabetes.  In two back-to-back sessions, we saw primary results from two cardiovascular outcomes trials (CVOTs): the CANVAS trial for J&J’s SGLT-2 inhibitor Invokana (canagliflozin) and the DEVOTE trial for Novo Nordisk’s Tresiba (insulin degludec). We also were treated to additional analyses from the LEADER trial of Novo Nordisk’s GLP-1 agonist Victoza (liraglutide, first presented at ADA 2016). Further, we saw results from the ODYSSEY DM program, evaluating the LDL cholesterol reduction efficacy of Sanofi’s PCSK9 inhibitor Praluent (alirocumab) in patients with diabetes). And finally, within the type 1 diabetes realm, the long-awaited results from the JDRF-sponsored REMOVAL trial of metformin in type 1 diabetes – which featured a primary endpoint of carotid intima media thickness (cIMT), a surrogate marker for CV risk – were a source of great interest as well. Beyond these highly-anticipated clinical trial findings, a separate symposium dedicated to discussing the role and future of CVOTs in diabetes care (including commentary from the highly-respected Dr. Lawrence Leiter) was a major highlight of the very first day of ADA – and this symposium, too, featured new data from the SUSTAIN 6 CVOT of Novo Nordisk’s once-weekly GLP-1 agonist semaglutide, delving into the retinopathy and weight loss findings further.
• While CVOTs were designed to demonstrate safety in CV endpoints, the long-term and largescale nature of these trials has yielded a bounty of data on other findings, including renal outcomes and hypoglycemia. The 2017 ADA meeting offered an equal focus on these exciting additional findings from CVOTs. The major headliner of the DEVOTE trial, rather than the CV safety of Tresiba, was the evidence that Tresiba substantially reduces severe hypoglycemia risk by 40% and nocturnal severe hypoglycemia risk by 53% compared to Sanofi’s Lantus (insulin glargine). The LEADER trial has also previously suggested a hypoglycemia benefit for Victoza and two separate sessions at ADA delved into the possible connection between hypoglycemia risk reduction and cardioprotection in the trial (a symposium featuring Dr. Stephen Bain and an oral presentation by Dr. Bernard Zinman) – spoiler alert, hypoglycemia was not a mediating factor of the CV benefit observed in the trial, though it is an important independent risk factor for CV events. We certainly had not expected to learn about amputations, and the fact that we did reinforces further the value of CVOTs.
  
  • Renal endpoints were of major interest both in CVOTs and in shorter trials. One of the other big headliners of the CANVAS data was the impressive renal benefit that corroborated the benefit observed for Jardiance in EMPA-REG OUTCOME – in CANVAS, Invokana therapy was associated with a 40% risk reduction for a composite renal endpoint (renal death, renal replacement therapy, or 40% reduction in eGFR). While the trials and endpoints are not really comparable, the EMPA-REG OUTCOME trial demonstrated a 39% risk reduction for a composite endpoint of progression to macroalbuminuria or doubling of serum creatinine accompanied by eGFR ≤45 ml/min/1.73 m2 or renal replacement therapy or death due to renal disease. Outside of CVOTs, we saw intriguing data from the AWARD-7 trial, which compared Lilly’s GLP-1 agonist Trulicity (dulaglutide) head-to-head with insulin glargine, both on top of insulin lispro therapy. While the primary glycemic endpoint results were comparable, Trulicity was very intriguingly associated with a potential preservation of eGFR throughout the trial. We’re certainly looking forward to the REWIND outcomes trial for Trulicity to further investigate the impact of this therapy on renal outcomes.
• We were also pleased to see an increasing focus on patient-reported outcomes in diabetes clinical trials. The very well-attended symposium highlighting new data from the LEADER trial featured patient-reported outcomes results as well – liraglutide demonstrated superiority in both the European Quality of Life (EQ-5D) index score (p=0.020) and the EQ-5D visual analog scale (VAS) score (p=0.019) and we were extremely pleased to see the inclusion of patient-reported outcome measures in one of the largest trials of a GLP-1 agonist to date. Novo Nordisk certainly appears to be becoming a leader (no pun intended) in this field – also at ADA, the company featured two posters highlighting patient-reported outcome data for Xultophy (insulin degludec/liraglutide) and Tresiba (insulin degludec). We think patient-reported outcomes and other measures beyond A1c are especially crucial to demonstrate the value of next-generation diabetes therapies like these and we’re so glad that Novo Nordisk is already incorporating this into its trials. We would like to see far more standardization on this front and hope that this is coming soon.  

Class Effects?

• More than ever, the diabetes field must grapple with the question of whether clinical trial findings – both positive or negative – can be considered class effects. On the one hand, we received confirmation that the cardiovascular and renal benefits of SGLT-2 inhibitors are very likely applicable to the entire class: the CANVAS trial demonstrated a remarkably similar reduction in risk for three-point MACE (non-fatal MI, non-fatal stroke, and CV death) for Invokana therapy as the EMPA-REG OUTCOME trial demonstrated for Jardiance. Like EMPA-REG OUTCOME, CANVAS also demonstrated a potential renal-protective benefit for the SGLT-2 inhibitor as well. Further corroborating the evidence that CV benefit is very likely a class effect, ADA 2017 featured additional analyses of the CVD-REAL massive, real-world, observational study that suggested a consistent cardioprotective effect across the class, in a data set of largely people taking Invokana or AZ’s Farxiga (dapagliflozin).
• On the other hand, there does appear to be some heterogeneity in individual components of the primary endpoint, as well as heterogeneity in safety signals. Most notably, the full CANVAS integrated program dataset revealed a roughly two-times increased risk for lower-limb amputations with Invokana compared to placebo – this safety signal came as a surprise, especially as it has not been identified in any previous trials of any SGLT-2 inhibitor, including the largescale EMPA-REG OUTCOME trial. The safety signal is particularly worrisome because there is no clear mechanism or consensus of understanding of what might be driving the increased risk. It’s not clear if the heterogeneity observed in SGLT-2 inhibitor trials thus far regarding this risk may be due to differences in trial design (be it patient population or adjudication methods or something else) or due to differences in the molecule. In any case, there are plenty of remaining mysteries and questions to keep us very, very invested in seeing the results from the DECLARE (April 2019) and VERTIS CV (October 2019) trials.
• To date, we’ve seen topline or full CVOT results for two SGLT-2 inhibitors, three DPP-4 inhibitors, and five GLP-1 agonists. Within every class, there appears to be some heterogeneity in either primary endpoint efficacy, safety concerns, or both. As discussed above, the SGLT-2 inhibitors demonstrated remarkable consistency in terms of CV and renal efficacy, but also hinted at serious differences in safety. Among the DPP-4 inhibitors, CVOTs demonstrated some heterogeneity in the secondary endpoint of hospitalization for heart failure, with both AZ’s Onglyza (saxagliptin) and Takeda’s Nesina (alogliptin) suggesting an increased risk while Merck’s Januvia (sitagliptin) was resoundingly neutral. That said, all three DPP-4 inhibitors with results thus far have reported CV neutrality for the primary endpoint of three-point MACE (non-fatal MI, non-fatal stroke, and CV death). Finally, we’ve seen quite a bit of heterogeneity within the GLP-1 agonist class over the question of cardioprotection – both the LEADER and SUSTAIN 6 trials for Novo Nordisk’s Victoza (liraglutide) and semaglutide demonstrated substantial CV benefits, but CVOTs for Sanofi’s Adlyxin (lixisenatide), AZ’s Bydureon (exenatide once-weekly), and Intarcia’s ITCA 650 (implantable exenatide mini-pump) have only demonstrated CV safety but not superiority (that said, Intarcia’s FREEDOM-CVO was a very small, pre-approval safety study that was not powered to demonstrate superiority). All in all, it appears that class effects for diabetes drugs cannot be taken for granted and it doesn’t seem to us that different agents within the same class are largely interchangeable. We hope that this key point can be effectively conveyed to providers and especially payers – in an era when formulary access, reimbursement, and rebates too often determine which drugs a particular patient takes, we hope that payers and PBMs recognize that the benefit-risk ratio for different agents can be quite different and do not force all their member patients to potentially take a less beneficial or even potentially harmful agent en masse. It’s clear that certain agents may be more helpful for some patients and a key cornerstone of therapy individualization is access to multiple options.

Combination Therapy Data Galore

• Some of the most exciting phase 3 results presented at this year’s Scientific Sessions dealt with combination therapy – GLP-1 agonist/basal insulin, GLP-1 agonist/SGLT-2 inhibitor, SGLT-2 inhibitor/DPP-4 inhibitor, and the list goes on.
  
  • Several exciting trials further characterized the clinical benefits of GLP-1 agonist/basal insulin combinations. This was the first ADA meeting with two such fixed-ratio combinations on the market, as both Sanofi’s Soliqua (lixisenatide/insulin glargine) and Novo Nordisk’s Xultophy (liraglutide/insulin degludec) were approved in November 2016 (on the same day, in fact). Full results from DUAL VII made headlines on Saturday, with Xultophy showing superiority to basal-bolus therapy (insulin glargine/insulin aspart) on critical outcomes beyond A1c, from hypoglycemia, to daily insulin dose, to weight loss. Xultophy was associated with an 83% risk reduction for hypoglycemia (p<0.0001), a mean 40-unit daily insulin dose vs. 84 units on a basal-bolus regimen (p<0.001), and a mean ~2 lbs weight loss over 26 weeks vs. ~6 lbs weight gain on basal-bolus treatment (p<0.001). A separate, late-breaking poster highlighted the patient-reported outcomes from DUAL VII as well – we were very pleased to see patient-reported outcomes highlighted in this way! Looking to co-administration (rather than fixed-ratio combinations), AZ shared promising efficacy data from DURATION-7, which compared GLP-1 agonist Bydureon (exenatide once-weekly) vs. placebo added to background insulin therapy. After 28 weeks, Bydureon demonstrated greater A1c-lowering efficacy (-1.0% vs. -0.3% from a baseline 8.5%; p<0.01) as well as greater weight loss efficacy (-3.3 lbs relative to placebo; p<0.001). Notably, 20% more participants randomized to Bydureon vs. placebo achieved the composite endpoint of A1c <7% with no weight gain or severe hypoglycemia.
  • The co-administration of GLP-1 agonists and SGLT-2 inhibitors is a hot topic in the diabetes field, and new data at ADA 2017 only added fuel to the fire. The full 52-week results from the DURATION-8 trial extension (initial 28-week data was presented at EASD 2016) was a highlight of this meeting. Presented in a late-breaking poster, the findings showed how co-administration of Bydureon/SGLT-2 inhibitor Farxiga (dapagliflozin) results in superior A1c-lowering, weight loss, and blood pressure-lowering vs. either drug alone. After 52 weeks, dual therapy resulted in a mean 1.8% A1c reduction vs. 1.4% with exenatide monotherapy and 1.2% with dapagliflozin monotherapy (p<0.01 for both comparisons). Weight loss was an average ~7.2 lbs on dual therapy vs. ~3.3 lbs on exenatide monotherapy and ~5 lbs on dapagliflozin monotherapy (p<0.001 for both comparisons). As Dr. John Buse pointed out during a separate session, one dedicated entirely to combination treatment approaches, the weight loss benefits in DURATION-8 seem to be more additive than the glycemic benefits, since A1c-lowering is a more baseline-dependent measure. Dr. Buse suggested that the true value of GLP-1 agonist/SGLT-2 inhibitor regimens may manifest in body weight effects more so than in glycemic effects.
  • Even ahead of the regulatory approval for Merck/Pfizer’s SGLT-2 inhibitor ertugliflozin, the scientific focus for the franchise seems to be the fixed-dose combination with DPP-4 inhibitor sitagliptin (Merck’s Januvia). ADA presentations from this clinical program included trial extension data from VERTIS FACTORIAL, comparing ertugliflozin/sitagliptin vs. each monotherapy, and from VERTIS SITA2, investigating ertugliflozin as an add-on to sitagliptin/metformin. Both studies highlighted superior glucose-lowering and weight loss efficacy from the combination vs. either drug alone, and both oral presentations emphasized the real-world value of a single, convenient oral tablet that combines two agents with complementary mechanisms of action.
• Notably, in all these data-heavy presentations on combination therapy, there was a distinct emphasis on outcomes beyond A1c. Most of these diabetes drugs were, or will be approved based on superior A1c-lowering vs. placebo. Once these products are on the market, however, we’d love to see them used optimally, which more often than not involves combination with another, complementary agent as well as advice on diet, exercise, mental health, etc. Patients with diabetes care about so much more than A1c: they want to experience weight loss, they want smaller postprandial glucose excursions, they want lower cholesterol and blood pressure, they want to live without fear of hypoglycemia. Combination therapy is one way to achieve better outcomes across the board, as this collection of data from ADA 2017 seems to show (results from the VERTIS program, DUAL VII, DURATION-7 and -8, etc.). Insulin will be necessary for type 1 patients, and for type 2 patients in later stages of the disease, but co-administration of a GLP-1 agonist could lower daily insulin dose, could bring down hypoglycemia risk, and could at least neutralize weight effects without sacrificing glycemic control. Formulations of two drugs in one – either fixed-ratio injectable combos or fixed-dose oral combos – come with the additional benefit of patient convenience (lower injection/pill burden) and a single co-pay. We were pleased to see so much new data on combination therapy packed into the ADA 2017 agenda, and were happier still to note how scientists, researchers, and thought leaders are promoting combination approaches in terms of outcomes beyond A1c. It has been distressing, however, to see commercial uptake so low – this is the fault of the payers as we understand it (not to be too reductive).
• Repeatedly, thought leaders – including Dr. James Gavin during a Monday-morning symposium dedicated to combination therapy and Drs. Julio Rosenstock and Melanie Davies during an AZ-sponsored symposium – framed combination treatment as a solution to therapeutic inertia in diabetes care. We should listen to these leaders more! It makes perfect sense – if patients and healthcare providers struggle to add or intensify medications, treatment guidelines should encourage earlier use of combination therapy to circumvent the problem entirely. Step one, according to Dr. Gavin, is abolishing the treat-to-fail paradigm in diabetes management, and we couldn’t be happier to see it go – how great would this be! Dr. Gavin explained how a chronic disease as complicated as diabetes, which implicates the ominous octet as well as the microbiome, immune system, and glucose absorption in the stomach/small intestine, cannot possibly be managed by a single agent. He generated a sense of urgency around the need to move up combination therapy in algorithms, and drew a fascinating parallel to hypertension, a therapeutic area in which guidelines recommend initial combination treatment for 75% of patients. Drs. Rosenstock and Davies gave a joint presentation during an AZ-sponsored dinner symposium, highlighting the multifaceted benefits of a product that combines two agents with complementary mechanisms of action. For healthcare providers who see patients coming in with very high A1c at first visit, they suggested that the path forward is clear: Why try medications in a stepwise fashion, when we have combination agents in our therapeutic arsenal with demonstrated efficiency? We’re hearing an increasing number of expert opinions in support of earlier intervention with combination therapy, and all in all, we left San Diego with a lot of optimism on this front. We hope to see continued focus on the advantages of combination treatment at other diabetes conferences and at future ADA Scientific Sessions.

Progress on Adjunct Therapies for Type 1 Diabetes

• ADA 2017 featured substantial forward momentum on adjunct therapies for type 1 diabetes. Particularly notable were the suite of results for Lexicon/Sanofi’s SGLT-1/2 dual inhibitor sotagliflozin in type 1 diabetes. Across two oral presentations and two posters, Lexicon shared full data from the phase 3 inTandem1 and inTandem2 trials, as well as the phase 2 inTandem4 dose-ranging study and a JDRF-partnered phase 2 study in young adults with poorly-managed type 1 diabetes. inTandem1, a double-blinded trial that randomized 793 patients to either placebo, sotagliflozin 200 mg, or sotagliflozin 400 mg, impressively met its primary endpoint on top of optimized insulin therapy by producing a mean placebo-adjusted A1c reduction of 0.35% in the 200 mg arm (baseline A1c post-optimization=7.6%; p<0.001) and 0.41% in the 400 mg arm (baseline A1c post-optimization=7.6%; p<0.001) at 24 weeks. More than twice as many patients achieved net benefit (defined as the percentage of patients with A1c <7% at 24 weeks and no episodes of severe hypoglycemia or DKA during the study period) on sotagliflozin 400 mg compared to placebo: 44% and 34% of participants in the 400 mg and 200 mg arms respectively achieved net benefit at week 24, compared to just 22% of those in the placebo arm (p<0.001). Patients taking sotagliflozin further experienced a 1.6 kg (3.5 lbs) and a 2.7 kg (6 lbs) weight reduction at 24 weeks with the 200 mg and 400 mg doses, respectively – this compares to a mean weight gain of 0.8 kg (1.8 lbs) in the placebo group (p<0.001). The similarly-designed inTandem2 study demonstrated significant A1c reductions of 0.36% (200 mg dose) and 0.35% (400 mg dose) with sotagliflozin vs. placebo (p<0.001) in patients with type 1 diabetes on optimized insulin regimens (baseline A1c = 7.7-7.8% after insulin optimization). In addition to this primary endpoint, 32% of patients in both sotagliflozin groups achieved the secondary endpoint of “net benefit”:. The phase 2 inTandem4 study demonstrated statistically significant improvements in A1c and key primary endpoints such as secondary urinary glucose excretion, postprandial glucose, body weight, fasting plasma glucose (non-inferior), and blood pressure for sotagliflozin over placebo. Very notably, Lexicon shared data on beta-hydroxybutyrate (BHB) levels at baseline and at week 12 – as a measure of ketogenesis, BHB measurements are very helpful as we consider the potential DKA risk of sotagliflozin. Notably, the mean increase in blood BHB at week 12 was only 0.1 mmol/l, which is the lowest value detectable by a point of care BHB meter. Dr. Paul Strumph, Lexicon VP of Clinical Development, noted that this level of BHB increase is lower than what is typically seen with selective-SGLT-2 inhibitors – a promising nod toward a potentially better safety profile for SGLT-1/2 dual inhibitors like sotagliflozin in type 1 diabetes. Across these trials, there were fairly balanced adverse event rates across all three arms, somewhat higher rates of DKA with sotagliflozin, and somewhat lower rates of severe hypoglycemia. While there is some concern in some quarters about type 1 patients taking this class, there is no way to stop it so we advocate better education – as well, it may be valuable to look at gaps in therapy for type 1s in order to better understand patients taking SGLT-2 inhibitors off label. We applaud Lexicon for collecting so many outcomes and hope that these will be standardized soon.
  
  • A JDRF-partnered study of sotagliflozin in young adults with poorly controlled type 1 diabetes failed to demonstrate significant A1c reductions vs. placebo but showed promising improvements in other clinically relevant endpoints.  The trial enrolled 87 patients age 18-30 with type 1 diabetes and an A1c ≥9% and topline results were announced in December. Sotagliflozin produced placebo-adjusted A1c reductions of 0.35% (baseline = 9.7-9.9%) and the difference between groups was not statistically significant (p=0.10). However, sotagliflozin did appear to produce improvements vs. placebo on postprandial glucose, body weight, time in range, and A1c in patients with a baseline A1c of 9-10%. In addition, approximately 8 times as many patients in the sotagliflozin group achieved the “net benefit” endpoint of A1c <7% at 12 weeks with no severe hypoglycemia or DKA compared to the placebo group, though the absolute percentage of responders was low in both groups (16% vs. 2%). We were especially impressed by the CGM data from the study – sotagliflozin therapy produced a one-third increase in time spent in range of 70 mg/dl-180 mg/dl – mean proportion of time-in-range was 44% on sotagliglozin, compared to 33% at baseline. This study is a good example of the limitations of using A1c as the sole metric of efficacy for diabetes drugs, as other parameters like time in range and weight loss are likely more relevant for many patients.
• On the GLP-1 agonist front, the highly-anticipated  Lira Pump Trial demonstrated significant improvements in A1c, body weight, and time-in-range with liraglutide as an addition to insulin pump treatment in people with type 1 diabetes. People with type 1 diabetes using CSII and with overweight (n=44) were randomized to receive liraglutide 1.8 mg or placebo in addition to regular insulin pump therapy for 26 weeks. Compared to placebo, liraglutide as an add-on to insulin pump treatment produced significant improvements in A1c (-0.6% vs. +0.2%; p<0.001) and striking weight loss (-7.3 kg [16.1 lbs] vs. -0.6 kg [1.3 lbs]; p<0.001) results without increasing the time spent in hypoglycemia (3.2 vs. 3.5 events; p=0.77). While the A1c reduction may be perceived as fairly modest by some for a GLP-1 agonist, we’re especially impressed given the low A1c baseline, by the substantial weight loss, and by what increased time in ranges were. Excitingly, liraglutide as an add-on to insulin pump therapy gave participants significantly more time spent in the normoglycemic range (57% vs. 45%) – a crucial outcome for patient quality of life and perceived therapeutic and personal success. Currently approved for type 2 diabetes (under the trade name Victoza) and obesity (under the trade name Saxenda), these results underscore the potential of liraglutide for type 1 diabetes as well. We do remain confused that insulin use did not go down overall.
• In terms of novel therapies, Dr. Jeremy Pettus presented exciting phase 1 data on the last day of the conference demonstrating that a single dose of the human glucagon receptor (GCGR) antibody REMD-477 can produce substantial and long-lasting (weeks!) reductions in insulin requirements and improvements in glycemia and time-in-range in people with type 1 diabetes, without increasing hypoglycemia. In a double-blind study, people with type 1 diabetes (n=21) were randomized to receive a single subcutaneous injection of either 70 mg REMD-477 or placebo. One day following the injection, participants who received REMD-477 experienced a significant 26% reduction (12 units) by the second day after the injection (p=0.02). Furthermore, REMD-477 produced substantial reductions in average daily blood glucose concentration not days but weeks after the injection. For people in the treatment arm, average glucose fell 27 mg/dl in the first week post-injection (p<0.0010), -31 mg/dl in the second week (p=0.05), and -20 mg/dl in the third week (p=0.05). REMD-477 further produced substantial increases in time-in-range. In the week following the injection, participants on REMD-477 spent 71% of their time in normoglycemia (70-180 mg/dl), versus 56% for those on placebo (p=0.0001), and the effect persisted into the second week post-injection (70% time-in-range with REMD-477, versus 57%; p<0.05). We are very moved by the sheer timescale of REMD-477’s powerful actions and eager to learn more about the upcoming phase 2 study, which according to Dr. Pettus will examine the effect of multiple weekly doses of the peptide drug. For good reason Dr. Pettus’ presentation was certainly one of the most highly-anticipated highlights of the President’s Oral Sessions – the very final event of ADA, highlighting particularly notable late-breaking abstracts – and we will be watching the progress of this work very closely. Although this work is clearly in its earliest stages, REMD-477 is a perfect exemplification of a patient-friendly diabetes therapy that optimizes important outcomes beyond A1c – namely time-in-range and a vastly reduced injection burden.
• On the less positive side, ADA 2017 also featured disappointing results for metformin therapy in type 1 diabetes, in one of the largest studies to-date of this popular medication in this patient population. The JDRF-sponsored REMOVAL study failed to meet its primary endpoint of improvement in mean carotid intima media thickness (cIMT), a common surrogate marker for CV risk. What’s more, the glycemic endpoint findings from REMOVAL were modest at best. While metformin adjunct therapy products statistically significant differences in A1c compared to placebo, the clinical significance of the reduction is somewhat debatable. From a baseline of 8%, patients on metformin experienced a mean A1c decline 0.24% greater than patients on placebo after three months (p<0.0001). This reduction seemed to attenuate over time – after 36 months, this treatment difference was 0.13% in favor of metformin (p=0.006), though A1c had risen above baseline for both groups. Further, the reduction of insulin dose in the metformin group was extremely modest (a 1.9 unit/day difference at the end of three years, p=0.0018) and the hazard ratios for minor and severe hypoglycemia actually had a point estimate favoring placebo (though the finding was not statistically significant). All in all, the authors of the study conclude that REMOVAL results do not support the assertion in current treatment guidelines that metformin causes a clinically-meaningful improvement in glycemic control for people with type 1 diabetes. Regarding the whole of the data, including the CV findings, independent commentator characterized the findings as “suggestive, but not conclusive.” Metformin is arguably one of the most commonly-used off-label adjunct therapies for type 1 diabetes currently and, thus, the results from this long-term study are particularly disappointing. We look to sotagliflozin and other SGLT-2 inhibitors, GLP-1 agonists, and other therapies yet on the horizon as being more promising for this population of high unmet need. Additionally, we also note that some of the “headlines” around this study were deceptive – we want to make sure patients get the real story on the value of metformin in type 1 based on this trial.

Disappointing to Mixed results on T1D Cures and Prevention

• It was a bleak meeting overall for type 1 cures and prevention, as readouts from numerous studies were disappointing at worst, and mixed at best.
  
  • The primary endpoint for TrialNet’s highly-anticipated Oral Insulin study – time from intervention to diagnosis in the primary stratum – was negative, but researchers saw an interesting signal in one of the secondary strata. The two cohorts are almost identical (mIAA and ICA antibodies or both GAD65 and ICA512 antibodies), but members of the primary stratum had first phase insulin response above threshold, while those in the secondary stratum had first phase insulin response below threshold. This seemingly small difference in disease stage had a huge impact on the efficacy of 7.5 mg oral insulin daily: Those in the primary stratum receiving oral insulin progressed to diabetes diagnosis at the same rate as those in the placebo group, while diabetes diagnosis in members of the secondary stratum receiving oral insulin was delayed by an average of 31 months (2.5 years!) vs. the placebo group. These results suggest to us that, perhaps, had people in the primary stratum not been treated until they had impaired first phase insulin responses, then they may have also benefited from the therapy. In a press conference the day prior, study PI Dr. Carla Greenbaum said that she was “flabbergasted” by this finding. Stanford’s Dr. David Maahs pointed out that the study was not a home run, but a 31-month delay to diagnosis in a specific cohort of patients is surely an incremental victory – for a young child, that delay could mean over 6,000 fingersticks not performed, and 930 nights during which a parent can sleep through the night without having severe hypoglycemia on the mind. None of the presenting experts had anything more than a hand-wavy mechanistic explanation for these surprising results: Dr. Greenbaum called attention to the fact that the participants in the second stratum who do progress to diabetes do so much faster, regardless of treatment group, than those in the other three groups. She suggested that there may be a “flare up” of the disease, as seen in MS and Crohn’s, during which immune intervention can prove beneficial. Meanwhile, Dr. Desmond Schatz hypothesized that some beta cell destruction (determined by impaired first phase insulin response) begets an enhanced immune response, which oral insulin can blunt. There’s obviously a lot of mechanistic research to be done, but we’re definitely intrigued by this specific cohort.
  • The DiAPREV-IT trial of Alum-GAD in children with multiple IAAs but no diabetes showed that the therapy was safe, but ineffective in delaying or preventing progression to diabetes. Given GAD-induced immune tolerance’s storied history, many had high hopes that this trial would deliver results, but the intervention demonstrated no tangible benefit. In addition, regardless of stratum (two antibodies, three to six antibodies) or baseline glucose tolerance, the absence of delayed progression held. That said, the study had a small sample (n=25 Alum-GAD; n=25 placebo) and was therefore not powered for these subanalyses – it may be worthwhile to conduct larger trials in attempts to unearth subgroups of responders.
  • Lastly, a JDRF-backed phase 2 study of Gleevec (Imatinib) in adults recently diagnosed with type 1 diabetes showed faint signals of beta cell protection. Over the year, the primary outcome, C-peptide AUC during a mixed meal tolerance test, declined steadily in the placebo group, while the group that received Gleevec followed the same trajectory for the first few months, before diverging and ending up with a statistically significant increase by month 12. While the findings are nowhere near definitive, highly regarded investigator Dr. Stephen Gitelman told us that the purpose of the study was to demonstrate feasibility to support future studies in pediatric patients, where he thinks the drug can have much more pronounced effects.
• It’s been a long time since we’ve seen a very positive biological study in type 1 diabetes – in fact our associates haven’t even been in diabetes long enough to see one. The above studies serve as a reminder as to how difficult it is to nail down a therapy as protective against diabetes. Assuming an efficacious compound is under investigation, zeroing in on effective dosing regimen, time and frequency of administration, and responding subpopulations is no easy feat. Boston Children’s Hospital’s Dr. Joseph Wolfsdorf put it beautifully: “Imagine in the 1930s,” he began, “when penicillin was discovered. It kills bacteria in a petri dish, so they started a trial with penicillin to kill streptococcal pharyngitis in the throat, 5 mg/day. What if the dose had been in the completely wrong universe? Are we struggling to make headway here because we don’t know how to dose the therapy?” It’s anyone’s guess, but at this point, we’ve sadly gotten accustomed to seeing late-stage failures, such as anti-CD3 therapies in the Protégé and DEFEND trials. When will the tide turn?
• As alluded to earlier, we were a little put off by somewhat misleading headlines in press releases announcing these trial results. For REMOVAL, the title read “Long-Term Metformin Treatment Found to Reduce Risk of Heart Disease in Adults with Type 1 Diabetes” – REMOVAL was not a cardiovascular outcomes trial, it failed its primary endpoint, and the main content of the ADA press release only mentions secondary/tertiary endpoints, which was very surprising. The DiAPREV-IT headline read “Autoantigen GAD-Vaccine is Safe for Children at High Risk for Developing Type 1 Diabetes” – while this is true and reflects the primary outcome of the study, it doesn’t disclose the more pertinent finding, that the vaccine did not prevent or delay the development of diabetes. So many people in our field our so busy and may not have the time to delve deeply into every email and press release that passes through their inboxes, so it is absolutely critical that the media is as transparent and accurate as possible. Further, we recently heard from healthcare journalists at the Spotlight Health conference that the proliferation of low-quality health news in the mainstream media is due in part to newer and less-trained journalists who rely heavily on press releases, rather than investigating the primary results themselves through journal publications, etc. We so appreciate the enormous support the ADA provides for press during its annual meeting each year – as we understand it, over 200 press correspondents were registered for the 2017 Scientific Sessions – and we hope to see greater attention paid to press release headlines in the future, given the immense responsibility entrusted to this organization.

Advances in More Patient- and Caregiver-Friendly Glucagon for Hypoglycemia

• Zealand and Xeris highlighted their continued progress on the liquid-stable glucagon autoinjector front at ADA 2017. In a poster, Zealand detailed phase 2 results from a PK/PD study of its liquid-stable glucagon analog dasiglucagon in people with type 1 diabetes (n=58), demonstrating that dasiglucagon, like native glucagon, can rapidly and effectively increase blood glucose concentration following a controlled, insulin-induced hypoglycemia event in which blood glucose fell to 55 mg/dl. On the pharmacodynamic front, the three highest dasiglucagon doses used in the study (0.3 mg, 0.6 mg, and 1.0 mg) each took a median of six minutes to raise plasma glucose levels to above 70 mg/dl, versus 6 and 7 minutes for the 0.5 mg and 1.0 mg doses of native glucagon, respectively. Notably, the increase in plasma glucose was longer-lasting and more pronounced with dasiglucagon; this larger glucose excursion profile promisingly suggests that dasiglucagon may be superior to native glucagon at preventing recurrent hypoglycemia. The FDA is expected to provide guidance on dasiglucagon’s development imminently. The candidate is currently in phase 2 development both as a single-dose rescue pen (phase 3 to begin as soon as 3Q17) and as a multi-dose component of a dual hormone artificial pancreas system. We were also pleased to get a glimpse at promising efficacy/safety results for Xeris’ G-Pen Mini mini-dose glucagon for both non-severe hypoglycemia events (1068-P) and for exercise-induced hypoglycemia (67-LB). All in all, we are very pleased to see this progress toward a more patient-friendly and feasible alternative to the current very complex, error-prone native glucagon kits – a longstanding area for improvement in diabetes care. This area is certainly heating up!
• We also heart exciting updates on the nasal glucagon front from Lilly. Dr. Elizabeth Seaquist presented positive real-world data on Lilly’s phase 3 nasal glucagon, showing that 96% of patients experiencing hypoglycemia recovered within 30 minutes following treatment and that most of the caregivers were highly satisfied with the device. The study enrolled 129 adults with type 1 diabetes, and 69 of these participants experienced a total of 157 symptomatic moderate or severe hypoglycemia events (a blood glucose of approximately <60 mg/dl or requiring assistance) during the course of the study. For 151 of these episodes (96%), a 3 mg dose of nasally-delivered glucagon met its primary endpoint of “awakening or returning to normal status” within 30 minutes, as determined by a caregiver. For five of the remaining six events, caregivers noted recovery within 45 minutes, and in four of these instances, the patient’s blood glucose was ≥70 mg/dl 30 minutes after administering nasal glucagon. A majority of caregivers, 70%, were able to deliver nasal glucagon to a patient experiencing hypoglycemia within 30 seconds, while 98% were able to do so in <2 minutes – what an exciting and much-needed improvement to the lengthy reconstitution process of existing glucagon options. The health and healtheconomic burden of hypoglycemia remains far too high, and we’re hopeful that advances like Lilly’s nasal glucagon will bring us leaps and bounds ahead in our ability to treat the complication.

Innovation in Rapid-Acting Insulin

• For the second year in a row, ADA 2017 featured more new, exciting data for rapid-acting insulins than for basal insulins. ADA 2016 was one of the first Scientific Sessions in recent history when this was the case, following several years of spotlight on new basal insulins (especially as next-generation Tresiba and Toujeo were getting approved). In the poster hall this year, Lilly’s rather secretive, internally-developed phase 2 ultra-rapid-acting insulin formulation drew much attention. The candidate LY900014, which contains citrate and trepostinil to speed insulin lispro absorption (and to make the analogue more physiologic), showed a superior PK profile (with faster onset/offset) and smaller postprandial glucose excursions vs. Humalog (insulin lispro) in both type 1 and type 2 diabetes. In the type 1 trial (n=30), the ultra-rapid formulation reduced time to half-maximal drug concentration by 36.5% (p<0.0001) and reduced total glucose excursion over a five-hour meal test by 44% (p<0.0001). In the type 2 trial (n=29), the phase 2 candidate reduced time to half-maximal drug concentration by 23% (p<0.0001) and reduced total glucose excursion over a five-hour meal test by 105% (p<0.0001). LY900014 could enter phase 3 by the end of 2017, and we’ll be eagerly following its clinical progress. Adocia also put up two posters on ultra-rapid BioChaperone Lispro, each sharing data from a 14-day study in type 1 or type 2 diabetes. The phase 3-ready candidate significantly improved postprandial glucose excursions vs. Humalog in both trials. In a surprise move, Lilly terminated its licensing partnership for BioChaperone Lispro in January, and it remains to be seen who will swoop in to carry the candidate forward through clinical (and hopefully commercial) development. Novo Nordisk’s Fiasp (faster-acting insulin aspart) is the first next-generation prandial insulin on the market in Europe, though we still await an FDA decision. We were pleased to see positive one-year efficacy data from the Onset 1 trial, in which Fiasp showed superior A1c-lowering (treatment difference of 0.1%) and one-hour postprandial glucose excursions (treatment difference of ~16 mg/dl) vs. insulin aspart – of course, not to be a broken record, but what we really want to see is time in zone, particularly given how strong the reception has been to Fiasp from patients (including Kelly, who loves the pens that she received). Lastly, we saw two posters from Sanofi on what could potentially become the first biosimilar rapid-acting insulin on the market – Insulin lispro Sanofi. Results from SORELLA 1 and SORELLA 2 (in type 1 and type 2 diabetes patients, respectively) support the phase 3 candidate’s similar PK profile compared to Humalog, and also demonstrate non-inferiority vs. Humalog on A1c.
• Clearly, rapid-acting insulin is a therapy area with substantial room for improvement. To that end, we’re happy to see ongoing innovation. While skeptics have claimed that Fiasp’s benefits over NovoRapid (insulin aspart) and other exiting prandial products are “incremental” rather than truly groundbreaking, we maintain that what we have right now is simply not good enough – so we’ll “more than” take incremental improvements, which for many patients appear to be quite meaningful. The faster onset/offset of Fiasp, Lilly’s phase 2 ultra-rapid candidate, and Adocia’s BioChaperone Lispro means lower risk of hypoglycemia and greater flexibility in bolusing, both of which are key variables in patient quality of life. Biosimilars are also promising in this era of skyrocketing insulin prices, so we look forward to the market potential of Insulin lispro Sanofi. That said, biosimilar basal insulin hasn’t been as cost-saving in the real world as initially anticipated (for many reasons, including unfamiliarity among providers), so our enthusiasm for Insulin lispro Sanofi is somewhat measured – though it’s possible we’ll seeing greater discounting with biosimilars once multiple biosimilar options are available. In either case, this will be a very interesting story to watch as it unfolds – Sanofi’s candidate received a positive CHMP opinion in May, recommending EMA approval, though there has been no word on plans for US submission.

Clinical vs. Commercial Enthusiasm

• As thought leaders sounded off on the latest and greatest in diabetes care at ADA 2017, we couldn’t help but notice some discrepancies between what scientists/researchers are most excited about and what’s being adopted by real-world patients/providers. A glaring example of this is combination therapy. We heard an abundance of enthusiasm on this front from diabetes experts, including Dr. John Buse, who advocated for greater uptake of fixed-dose and fixed-ratio combination products, and Dr. James Gavin, who advocated for earlier intervention with multiple agents (simultaneous as opposed to sequential treatment). On the other hand, patients/providers in the real world show a certain reluctance to combination therapy. In a separate call with our team, Dr. Sam Engel, Associate VP of clinical research in diabetes at Merck, attributed this hesitation to two factors: (i) HCPs feel obligated to up-titrate drugs to maximum dosage before trying something new, even though the majority of an agent’s efficacy will show at low- to mid-range doses. (ii) HCPs fear that it’ll be difficult to parse out the cause of adverse events if they start patients on more than one drug at a time, even though the side-effect profile of an agent is usually well-characterized prior to approval. Moreover, one of the distinct advantages to combo pills or injections is that each component comes at a lower dose, and the combination thus comes with a milder side-effect profile vs. either monotherapy. Guidelines are starting to evolve, and are recommending earlier co-administration of drugs for patients with A1c >9%, but it’ll take dedicated, concerted effort to educate diabetes care providers far-and-wide on the benefits to combination therapy. We see great potential for pharmaceutical companies to play a leading role in this education. Merck, for example, is already positioning its SGLT-2/DPP-4 fixed-dose combination (ertugliflozin/sitagliptin) high on the priority list within the ertugliflozin franchise – oral presentations on VERTIS FACTORIAL and VERTIS SITA2 both emphasized the convenience of a single, oral tablet that combines two agents with complementary mechanisms of action. AZ is also investing strategically in Qtern (dapagliflozin/saxagliptin) and hosted a corporate symposium at this meeting with lots of discussion on combination therapy as a means to circumvent therapeutic inertia. We’d love to see additional patient/provider education efforts outside the context of scientific meetings, from these and other companies with combo products in their diabetes portfolios.
  
  • Another (extremely unfortunate) clinical vs. commercial discrepancy involves sulfonylureas. Diabetes experts acknowledge the affiliated risk for hypoglycemia, weight gain, potential for beta cell burnout, and heightened CV risk. And yet, sulfonylureas remain a major part of treatment algorithms due to their generic status and low cost. While we can’t underplay the affordability factor, we also can’t emphasize enough the substantial downstream costs of severe hypoglycemia and CV events (hospital visits, emergency care, productivity loss, major adverse effects on patient quality of life, etc.). The ongoing CAROLINA and GRADE studies could produce the data we need to remove sulfonylureas from their current mainstream role in diabetes management: CAROLINA is Lilly/BI’s CVOT comparing DPP-4 inhibitor Tradjenta (linagliptin) vs. a sulfonylurea (glimepiride), expected to complete in March 2019 (which, suddenly, doesn’t seem that far away), and the GRADE study will analyze diabetes therapies head-to-head to determine the optimal combination treatment for long-term care. As newer classes like DPP-4 inhibitors, SGLT-2 inhibitors, and GLP-1 agonists approach generic status, we hold out hope that sulfonylureas will slowly but surely fall out of practice, yielding to superior therapies that offer A1c-lowering, weight loss, and other advantages to outcomes beyond A1c without conferring CV or hypoglycemia risks.

Insulin Pricing

• Insulin pricing continued to be a major focus at the ADA, where – for the third year in a row – a headlining symposium was dedicated to the topic at the Scientific Sessions. The symposium was chaired by Dr. Irl Hirsch (one of the first to sound the alarm bells on the insulin pricing controversy) and featured experts from all perspectives on the topic, including former ADA Chief Medical and Scientific Officer Dr. Robert Ratner, Yale’s Dr. Kasia Lipska, University of Kansas’ Dr. David Robbins, and pharmacist Dr. Alan Carter. Every speaker in the session acknowledged the complexity of the healthcare and drug pricing system and emphasized that no one stakeholder is the sole driver of increased prices. That said, there were varying degrees to which the presenters highlighted the role of pharmacy benefits managers (PBMs) and pointed the finger at pharmaceutical companies. Dr. Ratner, in particular, noted that rebates to PBMs rose substantially from $67 billion in 2013 to a whopping $106 billion in 2015 – leading him to suggest that we should get rid of these “middlemen with no added value increasing expenditures.” We aren’t sure they add no value, but we agree that we’d like to see more transparency. On the other hand, Dr. Lipska briefly acknowledged the role of PBMs in insulin pricing during Q&A, but largely described the role of what she termed “incremental innovation” and new patents from pharmaceutical companies in increasing the price of insulin. In terms of solutions, all speakers emphasized that “it takes a village” to substantially improve the financial burden of insulin for patients. Dr. Robbins in particular highlighted several things that individual healthcare providers, patients, regulatory agencies, pharmaceutical companies, and the FDA can do to improve this issue. For the field as a whole, Dr. Robbins asked all the various stakeholders to stop oversimplifying the issue of drug pricing and to share the blame, rather than point fingers. Further, the formation of partnerships to tackle this problem are crucial. He also emphasized the need to healthy, educated, and fair critics, while recognizing that we are all subject to bias. To that end, he emphasized that “new” is not always better. And finally, he called upon attendees to always advocate for their patients. Dr. Ratner looked at specific ongoing or proposed events and policies and their potential impact on insulin costs, including the arrival of more biosimilar competition, the proliferation of direct-to-consumer discount programs, lawsuits that force pricing transparency as part of discovery, and several proposed policy and legislative changes. All in all, it’s clear that the furor over insulin pricing has not abated, and we’re glad to see continued discussion of concrete solutions to help patients on this front.

Diabetes Technology

CGM Outcomes Standardization and Outcomes Beyond A1c

• Many in attendance felt that key stakeholders finally arrived at a consensus on standardizing CGM outcomes metrics during a Friday session chaired by Stanford’s Dr. Bruce Buckingham and our very own Ms. Kelly Close. Dr. Bruce Buckingham proudly proclaimed, “You were all in the room where it happened,” stealing a line from Hamilton. See the table below for the proposed metrics. During the session, a range of experts (Drs. Rich Bergenstal, Anne Peters, Thomas Danne, Simon Heller, George Grunberger, and Aaron Kowalski) all emphasized that A1c alone is not sufficient to guide next-gen treatment development, optimized care, regulatory approvals, reimbursement, and other important decisions. There have been nine CGM outcomes consensus statements since 2013, and Dr. Bergenstal thinks that we probably don’t need any more – it’s time to settle on the core metrics and move forward. Now that sensor technology has caught up to enable accurate tracking of time-in-range, hypoglycemia, hyperglycemia, and variability, implementation will be easier than ever before. We are elated with this progress, though we realize there much still needs to happen to make ensure that outcomes beyond A1c are reported in clinical trials, used as a basis for approval, and are included in product labels to drive better reimbursement. There has been so much discussion and so many stakeholders involved, and we’re glad to see meaningful progress on consensus. The terminology remains a point of debate (e.g., Level 1 hypoglycemia”), and we’ll hear much more at the July 21 gathering in Bethesda, Maryland on this topic (register here for free).  

Standardizing 14 Core CGM Metrics
Time in Range	70-180 mg/dl

Hypoglycemia	Level 1	<70 mg/dl
	Level 2	<54 mg/dl
	Severe	Clinical diagnosis: Event requiring assistance
Hyperglycemia	Level 1	>180 mg/dl
	Level 2	>250 mg/dl
	DKA	Clinical diagnosis: ketones, acidosis (hyperglycemia)
Glycemic Variability		Coefficient of Variation Standard Deviation (?)

Mean glucose	-
Estimated A1c	-
CGM Visualization	AGP
Episode of Hyperglycemia/Hypoglycemia	15 minutes
Sleep-Wake Time Blocks	12am-6am, 6am-12am
Data Sufficiency Recommended	Two weeks of collection 70-80% of CGM readings (minimum)

• In a separate talk’s Q&A, Dr. Peters remarked with a hint of cynicism: “I don’t know if I can get away with saying that we are following the wrong marker in clinical practice, but we need to consider other outcomes beyond A1c.” For providers, titrating therapies based on A1c alone can be misleading in a sizeable fraction of individuals, given all the inter-patient variability in glycation. Moreover, we like how time-in-range, hyperglycemia, hypoglycemia, and AGP are actionable on a titration basis – “Oh, you seem to be running high in the morning, let’s change X in your medication.” We expect the next-generation of therapies (e.g., closed-loop, SGLT-2s in type 1) will likely drive greater improvements in time-in-range than on A1c, and we hope regulators and payers appreciate the value accordingly.
  
  • A JDRF-partnered, 12-week study of Lexicon’s SGLT-1/2 inhibitor sotagliflozin in young adults with a high baseline A1c exemplified the importance of outcomes beyond A1c. The primary endpoint of A1c reduction was not met, but sotagliflozin did appear to produce improvements vs. placebo on time-in-range, postprandial glucose, and body weight. We were impressed by the CGM data from the study – sotagliflozin therapy drove a strong increase in time spent in range (70-180 mg/dl), which increased from 33% at baseline to 44% on sotagliflozin. That translates into an extra 2+ hours per day (!) spent in range, a very meaningful win for people with type 1. Under traditional criteria (A1c alone), this useful therapy might not move ahead for this populations. But with the tools available to now measure time-in-range, companies will be far better equipped to characterize more nuanced benefits of their therapies. We look forward to a world where glucose sensors are standard in trials of new therapies.
• In a HUGE victory for data standardization, Dexcom added the one-page AGP report to its Clarity data management software. It’s outstanding to see Dexcom incorporate the report following the 2012 IDC/Helmsley Charitable Trust expert panel on glucose data reporting, the subsequent publication of AGP in JDST/DT&T in 2013, the 2016 AACE Glucose Monitoring Consensus statement, Abbott’s incorporation of AGP into FreeStyle Libre’s software; additional AGP commitments at ADA 2016 from Roche, Glooko/Diasend, and Abbott (expanded); and about a month after Drs. George Grunberger and Vivian Fonseca co-authored an Endocrine Practice Letter to the Editor recommending standard AGP-like reports. Clinicians have told us for a long time that the AGP is a great way to display data and have one report to look at, regardless of the device. We love that the momentum continues to build and that more companies see the value of adding this report on top of their own innovative ways to display data – the field needs both standardization and innovation! Dr. Grunberger presented the idealized view of standardization in Dexcom’s press release, going back to a familiar analogy: “AGP can become the EKG report of diabetology - where there is one standard glucose report that all clinicians can interpret.” Yes! Will Medtronic also add AGP to CareLink, rounding out the major players?

Automated Insulin Delivery Field (Finally) Gets Commercial: Medtronic MiniMed 670G, Tandem PLGS, Insulet Horizon, Diabeloop

• The automated insulin delivery (AID) field took on a more commercial feel this year, led by the broader launch of Medtronic’s MiniMed 670G hybrid closed loop. The rollout to 20,000+ priority access program participants was announced at the start of FDA, and followed pivotal trial data shared at ADA one year ago and the earlier-than-expected FDA approval in September. At this ADA, we saw encouraging data from the 670G “customer training phase” (n=730), highlighting sustained glycemic improvements (from 63% -> 74% time in range, a 9-mg/dl improvement in mean glucose), time in Auto Mode (92%), and sensor wear time (95%) that resembled the pivotal study. Meanwhile, the MiniMed 670G product theater drew a standing-room-only crowd (five deep in the back!) to hear Drs. Rich Bergenstal and Jennifer Sherr share HCP tips, expectations setting, case studies, and CareLink reports. In other words, the discussion moved to, “How do we roll this product out in clinical practice?”, rather than, “Is this product coming?” On the marketing front, Medtronic blanketed the city with 670G ads, and the company’s during-ADA Analyst Briefing shared strong confidence in the device and patient enthusiasm so far. Medtronic believes it is “2-3 years ahead” of the competition (we think it’s less if companies hit their timelines), and a series of incremental improvements to the 670G are planned near-term (no specifics provided, but this should include pediatric approval and Bluetooth-connectivity, among others). The MiniMed 670G Priority Access Program launch is expected to run into the fall, and in parallel, Medtronic is taking orders for non-priority-access-program individuals that want to get on the device.  
• Also on the commercial side of AID, we saw very encouraging new data from other products in development: Tandem’s PLGS device, Insulet’s Horizon hybrid closed loop, and Diabeloop’s system. All showed strong outcomes on the algorithm front, with launches planned in the 2018-2019 time frame. We’re very glad to see the makings of (hopefully) a thriving commercial market where many products can compete – not just on algorithms and glycemic outcomes, but on the increasingly important metrics of device form factor, appeal to MDIs, user experience/interface, business model, connectivity/remote upgrades, ease of prescribing, and far beyond. We’ve been talking about the “academic research-commercial product chasm” in this field for years, and finally, it felt like this ADA had more tangible industry movement to get actual products to market. (See our competitive landscape here.) That said, the insulin pump field is also more challenging commercially – e.g., no updates from J&J, Roche was not even in the exhibit hall, Tandem’s stock price took a bit of a hit – and many players like Bigfoot are expanding to focus on MDI dose titration too. The latter is great to see, and it will be fascinating to see how patients segment between MDI+CGM+decision support and automated insulin delivery (pump + CGM).
• The closed-loop academic research community is looking ahead, with a focus on meals and exercise, algorithm personalization, and new populations (e.g., hypoglycemia unawareness, in hospital). With a pipeline of commercial products coming, we’ll be fascinated to see how the academic research community’s focus evolves – where can it push the field forward? How should dollars be allocated to closed-loop research to benefit the most people with diabetes? Our own Adam Brown raised this as a topic of panel discussion at the annual JDRF Closed Loop Research dinner: what will drive the field’s growth in the coming years, and how should the portfolio of research align? We were glad to see the Cambridge team again present highly compelling data on closed-loop in type 2s in the hospital (a major area of need and potential to save lots of nursing time), while the UVA group showed the clear value of closed-loop in those with hypoglycemia unawareness (significant benefits on time <70 mg/dl). For now, the leading academics continue to focus on optimizing algorithms, since obviously tighter control with less user hassle will be key for making the products as great as possible. Key areas of research on the radar include: making meal control more automatic (faster insulins, adaptive algorithms, other hormones like glucagon or amylin), adding sensors that can inform systems of activity (jury is still out on this one, since metrics like heart rate can be a false signal), and perhaps even implantable systems (faster meal response and less hypoglycemia, though obviously a different scalability question from current subcutaneous systems). The insulin vs. bihormonal debate was a bit quieter and more data-based this year, which is fantastic in our view – let head-to-head data drive what patients, providers, and payers prefer.

Steps Forward in Insulin Dose Titration: Common Sensing Shows the Value of Dose Capture on Pens, New Data from Hygieia and Sanofi, Bigfoot Acquires Timesulin, Partnerships Abound

• In one of the most important diabetes technology posters in our view, Joslin investigators shared observational data on Common Sensing’s Bluetooth-enabled GoCap pen cap to monitor insulin dosing and timing. The remote dose capture was paired with Dexcom’s G4 CGM data in 31 patients – 16 older individuals (mean age: 74 years) and 15 younger individuals (mean age: 28 years). Participants used the Bluetooth-enabled GoCap + a paired app for one month with Lantus and Apidra insulins (Sanofi funded the study), allowing investigators to collect combined injection and 14-day CGM data. Gocap identified that 12% of insulin injections were missed/under-bolused over one month, while 20% of injections were extra/over-bolused (relative to what was prescribed). In addition, nearly one in three (29%) basal doses were taken outside the ± 1-hour scheduled time window for taking Lantus. (The range was a remarkable 4%-89%, meaning some users almost always missed the window.) Over the 14-day CGM period, patients spent only 41% of each day in range (70-180 mg/dl), with a striking 107 minutes per day <70 mg/dl (7%) and more than 12 hours per day >180 mg/dl (52%). The three example CGM profile plots, combined with insulin injection data from Gocap, were also FASCINATING. Dr. Irl Hirsch frequently asserts that this dearth of information is the biggest gap in diabetes data – with products like the GoCap moving toward commercialization, providers will soon have the treasure trove of MDI dosing data in their tool belts.
• Also on the data front, Sanofi presented encouraging results on automated basal insulin titration in type 2 diabetes (My Star Dose Coach, LTHome), while Hygieia showed the results from an RCT of its d-Nav Insulin Guidance Service. Hygieia’s poster arguably showed the biggest headline improvement in outcomes – A1c declined a notable 1% in the d-Nav group at six months (baseline: 8.7%) vs. 0.3% in the usual care group (baseline: 8.5%) (p<0.0001). Sanofi’s 16-week AUTOMATIX study similarly showed that the My Star Dose Coach BGM with built-in automatic Toujeo titration is safe and effective: 34% of Dose Coach users reached their fasting target of 90-130 mg/dl without confirmed+severe hypoglycemia vs. just 15% of routine care users. The number reaching fasting target without severe hypoglycemia was also higher in Dose Coach users: 46% vs. 37% in routine users. Both groups also saw a 1% A1c reduction from baseline – obviously “routine” care in a trial undersells how much attention the control group received. A separate Sanofi study testing web-based insulin titration software (LTHome) in Canada highlighted the clear value of this field for HCPs and the healthcare system – automated basal insulin titration required fewer HCPs visits and lower costs compared to usual titration.
• There was also major M&A news on the dose capture/titration front: Bigfoot Biomedical acquired Timesulin, giving it a connected dose capture technology through which it can build an insulin titration service for MDIs (possible 2019 launch). Timesulin co-founder John Sjölund (who also has diabetes) joined the Bigfoot team as of ADA and will lead efforts to bring this service to injectors – what a coup for Bigfoot to acquire this valuable technology and smart leader and what a smart lateral expansion over its ongoing work to improve insulin delivery via a pump+closed-loop algorithms.
  
  • We also learned in hallway chatter that Novo Nordisk quietly launched a connected pen in Sweden just a few weeks ago – providers can reportedly read the current iteration via NFC, but a pen with Bluetooth connectivity is reportedly coming. This was alluded to in the Glooko partnership announcement in January, and we’re elated to see the insulin giant’s continued commitment to digital health.
  • Companion Medical reps in the exhibit hall indicated that they are essentially ready to launch the Bluetooth-enabled InPen, but are waiting to formalize partnership(s) before coming to market. Assuming it does launch this year, it will be the first connected insulin pen on the US market. How will it set the tone for this field?
• In the short time that we were in San Diego for the meeting, there were three major BGM-dose titration software partnerships: Ascensia + Voluntis; Amalgam Rx + Hygieia; and Glytec + AgaMatrix. Notably, Glytec and AgaMatrix already have a pilot of their integrated offering underway. These partnerships are proliferating, as illustrated by our crowded insulin dose titration competitive landscape – and they should be. Combining accurate, passively-collected glucose data with clinically-validated dosing algorithms should prove superior to manual dose titration, or at least equivalent in the best of cases. The service model for each of these integrations is still a clear question – presumably, the devices+software could be sold as a bundle (one product for one price), or the meters could simply be one of many devices that integrates glucose data directly into the titration algorithms. The reality is, insulin is a very dangerous drug most patients are not using it optimally, and data can help bring more to goal with less wild-guess dosing and hypoglycemia. This seems like the first wave of titration partnerships for BGMs, and we fully expect CGM companies like Abbott, Dexcom, and Medtronic to quickly move into this area.

The Value of Connected Devices – Enabling Real-World Data Collection and More Insightful Products

• This ADA brought some notable examples of passive data collection from connected devices driving valuable real-world insights and evidence. We saw brand new, encouraging data from Medtronic/IBM Watson’s Sugar.IQ app – relative to baseline metrics (one month prior), a small group of 81 Sugar.IQ users experienced a solid 37-minute/day improvement in time-in-range, an 11% reduction in sustained hypoglycemia (>120 minutes), and an 8% drop in sustained hyperglycemia (>120 minutes). Notably, within three days of the app delivering a pattern “insight,” 65% of users experienced fewer lows and 55% experienced fewer highs. (It’s unclear when Sugar.IQ will launch fully, but we assume the biggest gating factor is approval of the standalone Guardian Connect mobile CGM, which remains under FDA review and is currently in human factors testing.) Meanwhile, Abbott continued to share fascinating real-world data from a >55,000-user-strong cohort on FreeStyle Libre – increased scanning was linked to higher time in range and decreased time in hyperglycemia. We also loved the FreeStyle Libre country-by-country breakdown, data that is now possible to collect at scale and passively with connected devices! In insulin dose capture, a Common Sensing poster shared very eye-opening results that combined its Bluetooth-enabled pen cap with Dexcom CGM data – boy is this going to make the “invisible” data behind injections visible, driving meaningful dose titration and decision support. Roche and Livongo also presented encouraging data on their connected BGM platforms – A1c changes (-0.9% for Roche, -1.2% for Livongo), higher treatment satisfaction (Roche), cost savings (Livongo: $136 per member per month), and more. Connectivity is a must-have in devices in our view, and the next step will be building excellent systems around products that use the data in meaningful ways – driving more insight for patients/HCPs, collecting real-world evidence for payers, and better understanding real-world product use to inform design improvements.

Expanding CGM Adoption – Value in Type 2 Diabetes, HCP Prescribing, and Psychosocial Impact

• Drs. Bill Polonsky (BDI) and Jeremy Pettus (UCSD) debated use of CGM in type 2 – MDI, basal-only, and non-insulin – concluding it “will eventually become the standard of care for type 2 diabetes, especially as the technology becomes easier to use and less costly.” Obviously, those latter two caveats are critical and will drive the field’s expansion. The final slides shared six major points of agreement concerning the future of CGM in this population: (i) with proper support, CGM could become a powerful motivational tool in type 2 diabetes; (ii) innovative training materials are needed for type 2s; (iii) new methods for providing CGM feedback are needed; (iv) episodic use of CGM may be best for many type 2s; (v) much more evidence on CGM in type 2 is needed; and (vi) we need to determine which patient types will benefit (e.g., the disengaged, hypoglycemia prone, chronically poor glycemic control, those trying to select the best medication, etc.). We loved this list and completely agree with the key improvements that need to happen, particularly on ease of use (factory calibration will be critical), proper feedback mechanism (what to do with the data), and trials to support that this technology actually drives meaningful improvement. Of course, the path to “eventually” making CGM “standard of care” in type 2 diabetes will likely be a long one – after all, we’re only at an estimated ~15%-20% CGM penetration in US type 1s!
  
  • We believe intermittent-use products like Abbott’s FreeStyle Libre Pro and Medtronic’s iPro have encouraging potential in type 2 diabetes at a population level – even though they may not be as valuable for behavior change as real-time CGM, they will be FAR better than the current standard of care (barely any/no glucose data at all to make therapeutic adjustments). Indeed, several FreeStyle Libre Pro posters at ADA showed the value of this technology across the world, including in India. There was high enthusiasm about the Pro device in Abbott’s exhibit hall booth and corporate symposium. We’ll be fascinated to see what kind of business Abbott can build with this very intuitive, HCP/patient-friendly product.
  • A big question for type 2 diabetes and CGM will center on patient segmentation – who will benefit from professional CGM 1-3 times a year vs. 24/7 real time? What will the healthcare system pay for? What will patients be willing to pay for? Will comparative efficacy trials need to be done, and if so, who will run them? What novel business models are possible with factory calibrated CGM? For example, what about a mail order professional CGM service, where a sensor could be placed by the patient and mailed back for analysis, similar to 23andMe or Ubiome? What can professional CGM learn from other therapeutic areas, such as cardiology? How will Medtronic’s iPro3 stack up to Libre Pro? How quickly will Dexcom/Verily’s first-gen sensor drive into type 2 diabetes (launch expected by the end of 2018)?
• Additional analyses from Dexcom’s DIaMonD trial of CGM in MDI affirmed the value of real-time sensors in type 2 diabetes. Dexcom’s Dr. David Price shared combined type 1 + type 2 data from the DIaMonD study testing CGM (n=179) vs. SMBG (n=128) in MDIs, the first pooled analysis following type 1 results at ADA 2016 (later published in JAMA) and type 2 data at ATTD 2017. The combined outcomes were very consistent with the by-group data: from a pooled baseline A1c of 8.6%, CGM drove a 0.9% reduction in A1c at 24 weeks vs. 0.4% in the SMBG group (adjusted mean difference: 0.5%; p<0.001). Time-in-range metrics also strongly favored CGM – at 12/24 weeks (pooled), CGM users were spending 72 more minutes per day in range (70-180 mg/dl) vs. 9 fewer minutes in the SMBG group (p<0.001). Taken with the results of Abbott’s IMPACT and REPLACE, DIaMonD definitely shows the value of CGM in the type 1 AND type 2 populations on insulin, though we see incremental benefit to be gained once decision support is added. According to Dr. Price, type 2 results are currently pending publication, and we wonder if they could drive more reimbursement of CGM in the insulin-using type 2 population. In a huge twist of irony, Medicare (US) and Germany’s Federal Joint Committee have really taken the lead on this – both organizations have approved reimbursement of CGM in intensive insulin-using type 2s. (Of course, actually getting it reimbursed is proving to be another thing entirely.) Will private payers follow CMS/Germany’s decisions, particular once DiaMonD type 2 data is published?
  
  • A separate satisfaction analysis from the DIaMonD study reached a very important conclusion: contrary to common clinical belief, patients with type 2 on MDI are likely to find CGM at least as engaging and valuable as patients with type 1 diabetes. In fact, mean perceived benefits were significantly higher (p <0.05) among participants with type 2 vs. type 1. Here’s hoping these results spawn more studies that counter the conventional views!
• Provider anxieties surrounding the time, cost, and technological savvy associated with supervising CGM use continue to be an issue, based on T1D Exchange data from Stanford’s Dr. Molly Tanenbaum. Survey results suggested type 1 diabetes clinicians (n=209) can be divided into three distinct profiles related to CGM: 20% are “Ready” to prescribe, 41% are “Cautious,” and 39% fall in the “Not Yet” category. Clinicians who fall in the “Not Yet” bin have the hardest time keeping up with new technology, see the lowest proportion of patients with type 1 diabetes, and generally have inadequate clinic time in clinic to review CGM data. No surprise there. For “Not Yet” clinicians, Dr. Tanenbaum suggested ambitious systemic change – if possible, healthcare system barriers should be addressed to enable increased acceptance. Remedying hesitations for the other two groups is simpler: “Ready” clinicians should be encouraged to think about what’s working well, and what might change if uptake increases; the “Cautious” group should assess whether patient and provider barriers align and feel comfortable with education and coaching techniques. Indeed, the current model of prescribing and paying for CGM still demands additional effort from clinicians (prior authorizations chief among them), and hesitant HCPs must see a more clear cost-benefit win to make the prescribing leap. Clinical inertia also plays a big role in medicine and will continue to affect diabetes technology – CGM is still rarely/not covered in medical school, and older clinicians may have baggage from previous generations of the technology. Though CGM has been around for more than a decade, it really hasn’t come into its prime until the past five years. (And with connectivity and accessible data, it’s really only the past two years.)
• In a talk revolving around her often-raised motto, “right device, right time,” psychologist Dr. Katharine Barnard noted the importance of keeping psychosocial outcomes in mind. CGM has enormous potential, but it may not be the right tool for an individual troubled by accuracy issues, intruding alarms, on-body burden, and a “perfectionist” mentality. We see ALL of these as solvable barriers, since they revolve around sensor design, better wearables, and novel user experiences tailored to different individuals. For instance, could CGM have a “less engaged teenager” mode vs. an “über type A” mode? Now that products use smartphones for display, we hope to see different UI/UX evolve for different patient segments.

Remote Diabetes Coaching and Apps Galore in Poster Hall – Virta, Livongo, One Drop, Glooko, mySugr Seek to Augment Face to Face Care

• Remote coaching and digital health apps had a larger presence at this year’s Scientific Sessions, particularly in the poster hall – Virta Health, Livongo, One Drop, Glooko, mySugr, and others all presented abstracts. See some of the highlights immediately below, which don’t even include all the aforementioned work in insulin titration!
  
  • Virta shared highly anticipated one-year results from its type 2 diabetes program, combining a low-carb/high-fat diet (to induce nutritional ketosis) and tech-enabled remote care. In an interim analysis of 111 patients with data at one year, A1c dropped a significant 1.3% from a baseline of 7.4% (p<0.0001), and 58% of patients achieved an A1c <6.5% while taking no diabetes medications or metformin only. Wow! Insulin was reduced or halted in 97% of users, and weight was reduced an impressive 14% from baseline, equating to a mean 35 lbs of weight loss (from 255 to 212 lbs; p<0.0001).
  • Livongo presented its first (to our knowledge) ADA oral, showing that its cellular-enabled BGM + remote CDE coaching drove a 1.2% decrease in A1c, a 37% reduction in total cholesterol, and an 8.3% reduction in triglycerides relative to non-Livongo users. These clinical benefits translated to savings of nearly $140 per member per month. The company also had two posters: One randomized crossover trial (out of UMass) demonstrated slight improvements in A1c and treatment satisfaction attributable to Livongo use, and the other showcased a 1% drop in A1c (baseline: 8.5%). Addition of a connected scale also resulted in weight loss.
  • One Drop also presented two outcomes posters, adding to its growing cache of real-world outcomes data: A late-breaking abstract showed that use of the in-app Experts coaching/education resulted in a statistically-significant 0.8% A1c drop from baseline; a second poster highlighted notably decreased average blood glucose (from 195 to 166 mg/dl), more in-range BGs (from 48% to 64%), and fewer high BGs (from 51% to 33%).
  • Glooko and mySugr presented retrospective analyses of their digital platforms too, which individually now have more than 1 million users each! Both posters showed encouraging, albeit small, improvements in glycemia (mySugr on LBGI, Glooko on hyperglycemia). It’s clear that both companies have built diabetes data apps that resonate with big populations, though the analysis of these massive real-world datasets has not really been done. There is clear upside too from incorporation of decision support (e.g., insulin dosing), remote monitoring programs to prioritize care (Glooko’s Population Tracker, mySugr’s work in Germany), and more seamless connectivity that doesn’t require manual syncing. How much improvement in outcomes can these products drive? As both companies move into population management and more insightful analytics, will these analyses grow in size and robustness?  
• Data supporting remote coaching + connected devices is expanding, whether real-world results or more familiar clinical trials. We love the potential to scale care and add more real-time monitoring and continuity, though sustained engagement, demonstrated outcomes, and business models will be key questions. Moving ahead, we expect to see more automated, interactive, and insightful decision support systems that leverage AI, machine learning, voice, and multiple data streams (including non-diabetes streams). Ultimately, this field is not about data for its own sake, but providing guidance for patients and HCPs that result in better outcomes.

Companies are Getting the Message: User Experience, Patient Feedback, and Integration with Consumer Electronics Really Matters

• More than ever, device companies are hearing the message: user experience, patient feedback, and consumer electronics integration are critical. Dexcom secured Android G5 approval just before ADA and launched on the Google Play store shortly thereafter – the app already has between 500-1,000 downloads and received an update just after ADA on June 18. Also on the eve of ADA, Apple’s Worldwide Developer conference talked about Dexcom’s G5 on stage, which will communicate directly from transmitter-to-watch in the next version of WatchOS – talk about a victory for the patient experience and a major sign of Apple’s commitment to this partnership! Dexcom was a pioneer on mobile medical apps and it shows in the product’s continued uptake, particularly in MDI. The Clarity mobile app also got a terrific facelift, giving users expanded retrospective data reporting right on the phone. Insulet was a standout in this area too, headlined by a first look at the upcoming Omnipod Dash platform. The locked down Android phone has substantially upgraded the PDM user experience, while the next-gen Horizon system (putting automated insulin delivery on Dash) has undergone six usability studies already (31 unique participants to date, including some 670G users). Said Program Director of Advanced Technologies Jason O’Connor, “It’s so critical to not rush a product to market, just because it has functionality. It has to have the right user experience to deliver a product that is going to integrate into people’s lives. We may not be the first to market, but it does mean we’ll deliver an exceptional product.” Insulet has even solicited feedback from OpenAPS community members, which would have been unheard of a few years ago. Tandem’s compelling media day also reminded us that the Device Updater – allowing t:slim X2 pump users to upgrade their software from home, including to add G5 CGM integration and automated insulin delivery – will be a key differentiator going forward. We expect the most successful diabetes devices/apps will be driven by continuous software updating and learning from users, just as the most successful consumer technology is. That said, software is a whole different ballgame than hardware, and continuously building/maintaining apps for a growing number of devices can be burdensome – which companies will nail this?

The DIY Community Going Strong – Autotune, Loop, and Pushing Industry to Move Faster

• The do-it-yourself (DIY) community is still pushing the envelope of diabetes technology. Patient innovators Dana Lewis and Scott Leibrand shared a late-breaking poster on Autotune, an algorithm that automatically recommends changes in pump settings based on CGM data. Even in an engaged group of users, most found the recommendation helpful and have reportedly changed their pump settings accordingly. We also heard plenty of hallway chatter on Loop/RileyLink, the DIY system that runs hybrid closed loop off an iPhone app. Those we spoke to praised the overnight time-in-range, the algorithm’s customizability (e.g., set point, aggressiveness), the ability to bolus from an iPhone (with TouchID) or Watch, the on-phone user experience (showing exactly what the algorithm is doing), and seeing projected glucose after carbs are entered. At the Diabetes Mine D-Data Exchange, major industry players (Medtronic’s Dr. Fran Kaufman, Insulet’s Dr. Trang Ly,  Bigfoot’s Bryan Mazlish, Tandem’s John Sheridan) showed encouraging openness to engaging with the DIY and broader patient communities. We hope that moving forward, companies can give these innovators a “sandbox’ to play in, allowing lead users to help drive innovation. Dexcom is taking a lead on this with its developer APIs, which will launch later this year and allow third parties to access retrospective data (three-hour-delay), create and manage pre-commercial (prototype) apps, play with simulated (sandbox) data, learn how to become a Dexcom data partner, and even submit an app for commercial approval. Hopefully the time window will shrink, driving an ecosystem of useful real-time decision support. We’ll be fascinated to see how different companies harness the brilliance of this community – there is obviously a fine line to tread here, but one with significant upside in our view. 

New Devices in Exhibit Hall, but Clear Changes in Device Industry – Startups had Booths, While Roche Did Not Appear

• We were glad to see several notable new tech products in an ADA Scientific Sessions’ exhibit hall for the first time: Medtronic’s MiniMed 670G hybrid closed loop and Guardian Connect CGM for MDIs, Insulet’s new OmniPod Dash PDM, J&J’s OneTouch Via bolus-only patch insulin delivery device, Dexcom’s Android G5 and upcoming touchscreen receiver, and many others.
  
  • Medtronic’s newly launched MiniMed 670G was probably the most talked-about device at ADA 2017, drawing sizeable crowds to the booth and dedicated product theater. The on-device experience was what we expected – a definite pump screen and display improvement over older Medtronic pumps, but still definite room to improve on simplicity, a consumer-grade experience, and connectivity/remote software updates. The company is managing expectations well, though we’ll have to see what early reviews are like once it really rolls out.
  • Insulet’s new Omnipod Dash PDM won our award for most improved device, bringing marked advantages in user experience on the locked-down Android phone (FDA submission in 2H17). Insulet’s emphasis on leveraging user feedback really shined in its product theater and in-booth demonstrations. We think this device will be quite well received from the loyal Omnipod user base, and it clearly gives Insulet a logical path to add Horizon automation and concentrated insulin.
  • J&J’s OneTouch Via bolus-only insulin delivery patch device drew crowds to see the device in the flesh for the first time in an exhibit hall. Reps disclosed that the product’s updated manufacturing process (submitted in November) has received FDA 510(k) clearance, but did not give any specifics on the launch timing front. It was great to finally get to hold the device, and it was clear that booth-goers were intrigued – we overheard one who was amazed by the patch’s small form factor. 
  • Dexcom’s just-approved Android G5 and new touchscreen G5 receiver were on display for the first time following recent FDA approvals. We would describe the new receiver as “built like a tank” – it’s bigger than the current option, and the touchscreen is more resistive than one found on a consumer-grade phone. This thing looks like it could be thrown at the wall and not break, which brings two deliberate advantages: (i) fixing the reliability issues that have challenged Dexcom’s current receiver; and (ii) addressing the Medicare reimbursement requirement that the durable G5 receiver last for three years. (This latter point we only heard in hallway chatter.) We assume once this new receiver is out, more non-Medicare users will switch to displaying data on a smartphone – it definitely loses some cool factor relative to the current iPod Nano-like receiver.
  • Abbott’s FreeStyle Libre Pro and Tandem’s t:slim X2 were not new to US exhibit halls, but did draw notable crowds interested in the next-gen devices with meaningful improvements – the former to professional CGM and the latter to Bluetooth connectivity/remote software updating.
• One of our first observations upon entering the massive exhibit hall was: “Where’s Roche?” In fact, the major BGM player did not have a booth at this year’s conference to show off its new Accu-Chek Guide BGM or soft-launched Insight CGM system in Europe. This was not highly surprising from one perspective – it’s a tough time for Roche’s US BGM business and it has discontinued new US pump sales – but the juxtaposition with other players was noted. Glooko, Companion Medical, One Drop, and many other smaller device companies were indeed present in the massive ADA hall. This was perhaps a sign that: (i) Roche is being more choosey with its marketing resources (do exhibit hall booths have good ROI relative to other investments?); (ii) reflective of Roche’s smaller geographic sales base in the US; (iii) fewer new Roche products to showcase at this ADA; and/or (iv) something else. While bigger device companies like Medtronic, Abbott, BD, etc. were of course present in a big way in the hall, it felt like a greater number of small, innovative players were present this year and the average age is definitely younger! It will be fascinating to see how large AND small players drive innovation in the years ahead, and whether the current trends of tech partnerships will continue/increase at the next few ADAs. 

Additional Topics

Growing Focus on Diabetes-Adjacent Indications

• Repurposing existing diabetes drugs (either alone or in combination with another agent) for diabetes-adjacent indications like obesity, NASH, and prediabetes was another notable theme this year. On the SGLT-2 inhibitor front, we heard the results of a new sub-analysis of the EMPA-REG OUTCOME trial demonstrating the efficacy of Lilly/BI’s Jardiance (empagliflozin) to reduce adiposity as well as an oral presentation offering further phase 2 data on canagliflozin/phentermine combination therapy for obesity. Two posters additionally showed promising data on AZ’s Farxiga (dapagliflozin) for prediabetes and J&J’s Invokana (canagliflozin) for improved liver metabolism in people with obesity. Additional posters examined Merck’s Januvia (sitagliptin) and the TZD pioglitazone for prediabetes. GLP-1 agonists continue to show promise for obesity in particular: we were especially impressed by a meta-analysis of the entire SUSTAIN clinical trial program showing superior and clinically meaningful reductions n body weight across all five studies, versus a range of tested comparator drugs and in a broad range of patient populations. Novo Nordisk recently shared positive phase 2 topline data for a once-daily injection of semaglutide for obesity, demonstrating impressive mean body weight reductions of nearly 14% and we’re eager to see this investigated further. Novo Nordisk has a particularly robust early- and mid-stage pipeline for obesity and we’re looking forward to the newsflow on this front at future ADA meetings.
• There is also a great deal of activity on the novel therapy front for diabetes-adjacent therapies. GLP-1 agonist combination therapy appear to be all the rage, and we were especially intrigued by posters demonstrating the ability of GABA/GLP-1 combination therapy to prevent the onset of diabetes in animal models by promoting beta cell regeneration and the efficacy of a long-acting GLP-1/glucagon/GIP tri-agonist developed by Hanmi Pharmaceuticals. Reflecting the increasingly robust obesity drug competitive landscape, entirely novel therapies for obesity also have a strong presence at this year’s conference. Posters demonstrated impressive efficacy data for early drug candidates such as Janssen’s oxyntomodulin agonist XTEN and ProMetic’s anti-fibrotic compounds PBI-4547 and PBI-4050 for obesity. On the NASH front, we saw impressive preclinical data for PB-718 from a group in Suzhou, China, as well as Spitfire Pharma’s SP-1373.

A Welcome Increased Emphasis on Prevention

• We noticed a greater emphasis on prevention at this year’s ADA – a welcome sign of growing recognition of the importance of prevention efforts to combat diabetes on a population level. In fact, this was the central focus of this year’s Presidential Health Care & Education address in which Ms. Brenda Montgomery discussed the ADA’s pursuit of “pillars of prevention” in the form of prevention-related research and clinical trials, educational efforts, and political advocacy to establish Medicare coverage for the NDPP. To this end, we heard several notable presentations evaluating the efficacy of diabetes prevention approaches in different demographic subgroups over time. For instance, a 15-year analysis of the Diabetes Prevention Program (DPP) study reported that metformin has an enduring preventive effect for younger people, individuals with a greater BMI, and women with a prior history of gestational diabetes. Furthermore, we heard the highly-anticipated results of the PREVENT-DM study, the first comparative effectiveness trial of diabetes prevention treatments in a real world setting. In a population particularly vulnerable to type 2 diabetes (Hispanic females with low socioeconomic status), intensive lifestyle intervention delivered by community health workers produced significantly greater weight loss than metformin and standard of care, suggesting that such programs are an effective population-level strategy for diabetes prevention. Despite the growing conversation on diabetes prevention programs, the legendary Dr. Ann Albright, director of the CDC’s Division of Diabetes Translation, issued a compelling call for even greater effort on this front, arguing that “we need to address prevention to a much great degree than we currently are” in order to make a dent in the diabetes epidemic. Because policy and community-level strategies for prevention take place so incrementally, Dr. Albright offered a perspective for how to promote diabetes prevention in the context of one-on-one conversations in the physician’s office. She suggested tailoring conversation topics for people at different levels of diabetes risk – low (general information about healthy behaviors), medium (NDEP resources and recipe guides), and high (structured programs like the DPP, or medication like metformin).

Psychosocial Care in Diabetes

• This year marked the first time the Scientific Sessions have focused explicitly on psychosocial aspects to diabetes care. At a Friday press conference, Dr. Korey Hood (Stanford University, CA) reviewed the new ADA/APA (American Psychological Association) position statement on this topic, which also led the ADA to incorporate psychosocial support into its 2017 Standards of Care and to feature more research of this genre at ADA 2017. Most notably, the ADA Presidents Oral Session on Tuesday morning included Dr. Mary de Groot’s presentation of Program ACTIVE II study results. This trial randomized people with type 2 diabetes and clinical depression (n=150) to one of four arms for 12 weeks: (i) exercise with a personal trainer, (ii) talk/cognitive behavioral therapy, (iii) exercise plus talk/cognitive behavioral therapy, or (iv) usual care. All three interventions were associated with statistically significant improvements in depressive symptoms (p<0.05), diabetes distress (p<0.01), and quality of life (p<0.05) vs. usual care. Participants in any of the intervention groups also reported fewer negative automatic thoughts after 12 weeks (p<0.03 vs. usual care). These beneficial effects were sustained when controlling for antidepressant medication use, underscoring the efficacy of both exercise and therapy as approaches to psychosocial care. Drs. Hood and de Groot were both authors on the ADA/APA position statement, which they described as a major collaborative effort. The overarching goal outlined is to enhance training of mental healthcare professionals so they’re better-equipped to screen for and treat diabetes distress and comorbid diabetes/depression. That said, in order to broaden and maximize the impact of improved psychosocial care for a diabetes patient population, endocrinologists and primary care physicians who treat diabetes will also have to be trained to increase screening and referrals. “There’s a lot left to do,” Dr. Hood emphasized. The new position statement and higher number of related abstracts at this conference are small steps in the right direction. Next, the ADA/APA have to devise ways to make sure psychosocial care is implemented in a cost-effective and evidence-based manner, Dr. Hood explained – to this end, studies like Program ACTIVE II that identify specific, effective approaches to psychosocial support are so valuable. A follow-up meeting between the two professional organizations is scheduled for August 2017. We’re eager to see what comes of this partnership and position statement, and to observe positive effects in real-world clinical settings, though this will likely take some time. We’re glad to note ADA’s commitment to spreading awareness/education of the position statement on psychosocial care. The ADA’s Standards of Care, for example, are influential around the globe, and we so hope diabetes providers and mental healthcare providers alike take notice and change their practice to give patients the best possible comprehensive care.

ADA Pathway to Stop Diabetes Symposium

• As always, the ADA Pathway to Stop Diabetes symposium offered an inspiring glimpse into the future of diabetes management. Most notably, UNC’s Dr. Zhen Gu, co-founder of Zenomics, a startup recently awarded $5.8 million from MicroPort Scientific Corporation, discussed a variety of smart insulin delivery approaches currently being investigated in his lab. In his view, the main challenges facing the smart insulin field today are (i) achieving a fast response comparable to normal beta cell activity; (ii) avoiding hypoglycemia; (iii) achieving ease of administration; and (iv) ensuring biocompatibility. Overall, beyond Dr. Gu’s star power, the symposium boasted an impressive range of ongoing projects, from Dr. Daniel Ceradini’s work (NYU Langone Medical Center) investigating accelerated diabetic wound closure to Dr. Kathleen Page’s results (USC) on central adiposity in childhood as an early indicator of intrauterine exposure to gestational diabetes and maternal adiposity. Other highlights included Cornell’s Dr. Praveen Sethupathy, who discussed recent findings demonstrating how a high-fat diet contributes to small intestinal morphology and physiology, and UW’s Dr. Joshua Thaler, who remarked on astrocycte and microglial inflammatory signaling as it pertains to obesity susceptibility.

Award Lectures

• As always, the award lectures sparked inspiration amongst all who attended. Ms. Davida Kruger (Henry Ford Medical Group, Detroit, MI) delivered an absolutely  moving Outstanding Educator in Diabetes Award Lecture, detailing her impressive dedication to the field over the past 35 years. Columbia’s Dr. Domenico Accili discussed exciting developments in diabetes research, anticipating massive changes in the way diabetes will soon be managed. And, Ms. Brenda Montgomery, ADA President of Healthcare and Education, discussed the ADA’s noteworthy efforts in the fight to prevent diabetes. 
  
  • Diabetes educator extraordinaire Ms. Davida Kruger delivered the Outstanding Educator in Diabetes Award Lecture, providing insights on her role in the DCCT, as a nurse practitioner in diabetes, and as an ADA volunteer. Ms. Kruger stressed the increasingly important role of the nurse practitioner, presenting data showing that nurse practitioners make equally accurate diagnoses as physicians and are also more likely than physicians to provide health education and promotion, adapt medical regimens to the patient’s preferences, and listen more to the patient. Ms. Kruger closed by stating that the field “must remain open to all team members” and keep the patient at the “head of the team.” Ms. Kruger deservedly left the podium with a standing ovation, and our team joins the diabetes world in our deepest gratitude and admiration for Ms. Kruger’s incredible leadership and service to the field.
  • In this year’s inspiring Banting Medal for Scientific Achievement lecture, Columbia’s Dr. Domenico Accili presented his vision of a revamped toolkit for diabetes care in 2021, 100 years after the discovery of insulin: Prevention of beta cell de-differentiation, a gut-targeted Foxo1 inhibitor to coax gut cells into producing insulin in a glucose-dependent manner, and selective insulin sensitizers. The meat of his talk focused on dispelling the perception that beta cell failure is a consequence of beta cell death; rather, his data suggest that beta cell dedifferentiation is to blame. Dr. Accili sees a big opportunity here: If beta cells are not dead, but just quiescent as dedifferentiated of converted cells, then there’s a chance to restore beta cell health even after the onset of hyperglycemia. For type 1 diabetes, Dr. Accili’s lab has set sights on coaxing gut cells into producing insulin in a glucose-dependent fashion, and for type 2 diabetes, Dr. Accili explained that it is possible to modulate critical nodes of insulin signaling to dial up/down individual bio-responses, enabling selective reversal of insulin resistance. With a portfolio this lengthy and deep, we can’t think of anyone more deserving of this award than Dr. Accili – our only hope is that he sticks with it and delivers 2021: A Diabetes Odyssey.
  • Ms. Brenda Montgomery, ADA President of Health Care & Education, gave a speech on ADA’s efforts in the fight to prevent diabetes. Last year’s President’s address by Dr. Desmond Schatz, in which he pleaded with attendees to bring diabetes to “the boiling point of water where it erupts with urgency” was a tough act to follow, but Ms. Montgomery delivered. In particular, Ms. Montgomery focused on prevention, organizing her remarks in accordance with the ADA’s three strategic imperatives: (i) Drive Discovery, through research, partnership, and innovation; (ii) Raise Voice, to intensify the urgency around the diabetes epidemic and mobilize action; and (iii) Support People, to continually develop new and effective resources for people affected by diabetes. Ms. Montgomery characterized the ADA’s work in the prevention space as a story of “small steps leading to big rewards.” Though we have yet to see fruits from those labors, we certainly applaud and thank all involved for their time and effort.

SGLT-2 Inhibitors

Symposium: The Integrated Results of the CANVAS Program

Background to the Design of the Trials

Gregory Fulcher, MD (University of Sydney, Sydney, Australia)

Dr. Gregory Fulcher opened the symposium with a brief history of the SGLT-2 inhibitor drug class and of the FDA’s post-marketing CVOT requirement. SGLT-2 inhibitors work by increasing urinary glucose excretion, thereby lowering glucose levels in the blood. This mechanism gives reason to believe that SGLT-2 agents may be cardioprotective: For one, hyperglycemia in itself is a risk factor for CV events. SGLT-2 inhibitors also reduce blood pressure via osmotic diuresis, promote weight loss (by excreting more calories through the urine), and reduce albuminuria – each of these independently is a risk factor for CV morbidity and mortality, and there are hypotheses circulating in the diabetes field that SGLT-2 inhibitors (including canagliflozin) might confer CV benefit by attacking a variety of contributing risk factors. Importantly, this is all speculation at this stage, as research is ongoing to determine mechanism of cardioprotection. Switching gears, Dr. Fulcher described the intention behind the FDA’s post-marketing CVOT requirement, which went into effect in 2008 – these trials should demonstrate that a new anti-diabetic drug is not associated with an “unacceptable increase” in CV risk. The upper bound of the 95% confidence interval for hazard ratio on a primary CV endpoint (most often, three-point MACE consisting of non-fatal MI, non-fatal stroke, and CV death) must be <1.8 pre-approval in order to win marketing authorization. Post-approval, a larger, dedicated CVOT must demonstrate a hazard ratio <1.3 to convincingly show non-inferiority vs. placebo. The FDA does not explicitly encourage demonstration of CV superiority, which would be achieved by a hazard ratio and confidence interval bound under 1.0. Lastly, Dr. Fulcher reminded everyone that canagliflozin is branded as Invokana by J&J, and is approved in 100 mg and 300 mg oral doses.

Methods for the Trials and the Integrated Analyses

Kenneth Mahaffey, MD (Stanford University, Palo Alto, CA)

Dr. Kenneth Mahaffey provided an overview of the trial design and data analysis scheme. The CANVAS program studied a total of 10,142 people across the CANVAS (n=4330) and CANVAS-R (n=5,812) trials. After a two-week placebo run-in period, participants in CANVAS were randomized to 100 mg or 300 mg canagliflozin or placebo and participants in CANVAS-R were randomized to canagliflozin 100 mg (with optional up-titration to 300 mg) or placebo. As enrollment criteria, all participants had an A1c ranging from 7% to 10.5%, an eGFR >30 mL/min/1.73 min2, and were aged >30 years with a history of a prior cardiovascular event or >50 years with at least two cardiovascular risk factors. The primary outcome was 3-point MACE (the composite of cardiovascular death, non-fatal MI, and non-fatal stroke). Secondary outcomes included all-cause mortality and cardiovascular death. Exploratory outcomes included non-fatal MI, non-fatal stroke, hospitalization for heart failure, hospitalization for heart failure or cardiovascular death, total hospitalizations, albuminuria progression, albuminuria regression, and a renal composite endpoint encompassing 40% reduction in eGFR, end-stage renal disease, or renal death. Importantly, the CANVAS program employed a hierarchical statistical testing structure – thus, secondary endpoints were assessed in a pre-specified order and, if a secondary endpoint failed, all endpoint results following that one in the hierarchy would be considered only exploratory. On the statistics front, Dr. Mahaffey explained that across the entire CANVAS program data all participants on canagliflozin were pooled together such that the statistical analyses evaluated a “strategy of canagliflozin treatment” versus placebo, without differentiating between the 100 mg and 300 mg doses in CANVAS or the possible up-titration from 100 mg to 300 mg in CANVAS-R. 

Effects on Cardiovascular Outcomes

Bruce Neal, MB, ChB, PhD (The George Institute for Global Health, Sydney, Australia)

Dr. Bruce Neal presented the cardiovascular results from the integrated CANVAS and CANVAS-R program. The room waited with bated breath as Dr. Neal discussed the patient populations, baseline characteristics, and metabolic outcomes in the program (detailed below). Finally, Dr. Neal presented the primary three-point MACE (non-fatal MI, non-fatal stroke, CV death) endpoint: canagliflozin therapy was associated with a 14% risk reduction compared to placebo (HR=0.86, 95% CI: 0.75-0.97, p<0.0001 for non-inferiority, p=0.0158 for superiority) – and the room prompting burst into applause and cheers, interrupting Dr. Neal mid-sentence. With a rueful smile, Dr. Neal acknowledged that he had waited eight years for this moment – and the CV results at least were certainly worth the wait! By individual study, the hazard ratio point estimate for the primary outcome were fairly consistent across CANVAS (HR=0.88, 95% CI:0.75-1.03) and CANVAS-R (HR=0.82, 95% CI: 0.66-1.01), though the results were not significant for either trial individually (likely due to a lack of power). The trial just missed superiority for all-cause mortality (HR=0.87, 95% CI:0.74-1.01, p=0.24) – since this was the second endpoint in the pre-specified hierarchical testing structure, the other endpoint results can only be considered exploratory. 

• Hospitalization for heart failure: Very notably, canagliflozin was associated with a substantial and impressive 33% reduction in risk for heart failure (HR=0.67, 95% CI: 0.52-0.87). Canagliflozin also reduced risk for a composite endpoint of CV death/heart failure hospitalization by 22% (HR=0.78, 95% CI:0.67 to 0.91). Notably, the Kaplan-Meier curve for hospitalization for heart failure especially appeared to diverge early and drastically, mirroring the results we saw in the EMPA-REG OUTCOME trial for Lilly/BI’s Jardiance (empagliflozin).

• Individual components of MACE primary outcome: The hazard ratio for individual components of MACE trended in the right direction favoring canagliflozin, but none of them reached statistical significance even though three-point MACE did. For non-fatal MI, the hazard ratio was 0.85 (95% CI: 0.69-1.05). For non-fatal stroke, the hazard ratio was 0.90 (95% CI: 0.71-1.15). And for CV death, the hazard ratio was 0.87 (95% CI: 0.72-1.06).

• Canagliflozin produced pronounced effects on a number of metabolic and cardiovascular risk factors. The mean A1c difference between the canagliflozin and the placebo groups was 0.58% – canagliflozin produced a large drop in A1c within the first few months post-randomization that attenuated over the six year follow-up period. Canagliflozin also produced a mean placebo-adjusted systolic blood pressure reduction of 3.93 mmHg, which occurred early in the trial (within the first year) and was sustained throughout the six-year follow-up. Finally, participants on canagliflozin experienced a mean placebo-adjusted weight loss of 1.6 kg (3.5 lbs) that also occurred in the first year and was sustained throughout the follow-up period.
• Together, CANVAS and CANVAS-R enrolled 10,142 patients (4330 in CANVAS and 5813 in CANVAS-R). Across the program, 96% of participants completed the study and end-of-trial vital status was known for over 99% of participants. Mean follow-up across the program was 188 weeks – CANVAS initiated first and mean follow-up in that trial was 296 weeks, while mean follow-up in CANVAS-R was 108 weeks. At the end of the trial, 71% of canagliflozin and 70% of placebo patients remained on their assigned intervention.
• Baseline characteristics were well-matched between the combined canagliflozin arms and placebo. Mean age across the study was 63 years old, with a mean diabetes duration of 14 years. Very notably, about two-thirds of participants had a history of cardiovascular disease at baseline (and one-third had CV risk factors but no history of CV disease). 90% of participants in the canagliflozin group had hypertension at baseline (vs. 90% in the placebo group) and 14% of participants randomized to canagliflozin had heart failure at baseline (vs. 15% of the placebo group).
  
  • In terms of demographic baseline characteristics, about one-third of participants were female, nearly 80% of participants were white, and about 60% of participants were from North America or Europe. This is fairly typical for a global CVOT, though greater racial/ethnic and geographic representation in trials overall is needed, and we’d like to see this emphasized to a greater degree, particularly given the extent to which under-represented minorities have an outsized risk of type 2 diabetes and type 2 diabetes complications.
  • Participants in the CANVAS program were on a variety of background diabetes and cardiovascular medications. Nearly 80% of participants were taking metformin at baseline, about half were on insulin, 42%-44% were taking SUs, and 12%-13% were taking DPP-4 inhibitors. Notably, only 4% of participants in each arm were taking a GLP-1 agonist at baseline – we would love to see an analysis of cardiovascular and other outcomes in patients on dual canagliflozin and GLP-1 agonist therapy, but we assume that the small number of participants in this subgroup would make such an analysis difficult. In terms of cardiovascular medications, nearly 75%-80% of participants were on RAAS inhibitors, statins, and antithrombotic agents, respectively. A little more than half were on beta blockers and a little less than half were taking a diuretic.
• Dr. Neal also presented several subgroup analyses that probed the potential for heterogeneity of effect among different patient populations. The p-values for interaction were all non-significant for age (<65 years old or ≥65 years old), sex, race (White, Black/African American, Asian, or other), and region (North America, Central/South America, Europe, and Rest of the world). Similarly, there was no significant interaction for various risk factors, including BMI, blood pressure control, duration of diabetes, A1c, or eGFR. The primary outcome benefit was also consistent regardless of CV disease, peripheral vascular disease, heart failure, or amputation history.
  
  • In fact, the only potential heterogeneity of effect was observed in two background therapy subgroups. Those taking beta blockers at baseline were significantly more likely to benefit from canagliflozin therapy than those who were not (HR=0.75 for those on beta blockers, 95% CI: 0.64-0.88 vs. HR=1.04 for those not on beta blockers, 95% CI:0.85-1.28, p=0.01). Furthermore, the heterogeneity of benefit was even more pronounced among the subgroups of those taking or not taking a diuretic at baseline: the HR for those on a diuretic was 0.66 (95% CI:0.56-0.79) and the HR for those not on a diuretic was 1.11 (95% CI: 0.93-1.34) – the p-value for interaction was a highly-significant p<0.001. There was no significant difference in benefit among subgroups of patients taking insulin, statins, antithrombotic agents, or RAAS inhibitors at baseline.  

Effects on Renal Outcomes

Dick De Zeeuw, MD (University Medical Center Groningen, Netherlands)

Next up, Dr. Dick De Zeeuw presented the effects of canagliflozin on renal outcomes. To complement its impressive cardioprotective effects, canagliflozin also showed signs of renal protection, including a 27% risk reduction for progression to albuminuria (HR=0.73, 95% CI: 0.67-0.79), a 70% increase in the regression of albuminuria (HR=1.70, 95% CI: 1.51-1.91), and a 40% risk reduction for the composite endpoint of renal death, renal replacement therapy, or 40% reduction in eGFR (HR=0.60, 95% CI: 0.47-0.77). Canagliflozin was further associated with an 18% (95% CI: -16% to -20%) reduction in urinary albumin:creatinine ratio (UACR). For the subset of participants with microalbuminuria and macroalbuminuria, canagliflozin decreased UACR by 34% and 36%, respectively. Together, these results suggest a potential renal-protective effect of canagliflozin treatment in people with type 2 diabetes, and Dr. De Zeeuw underscored these findings as a highlight of the CANVAS and CANVAS-R integrated full results. This data is particularly impressive in light of the fact that the CANVAS program enrolled a low renal risk population in which 70% of participants had normoalbuminuria (an albumin:creatinine ratio <30 mg/g) and a sizeable proportion had a normal eGFR (25% and 24% of participants in the canagliflozin and placebo arms respectively had mean eGFR >90 ml/min/1.73 m2, and 56% and 54% had mean eGFR between 60-90 ml/min/1.73 m2). Our curiosity is piqued for J&J’s CREDENCE trial investigating Invokana specifically for renal outcomes in patients with type 2 diabetes and diabetic kidney disease (expected to complete in June 2019).

Effects on Safety Outcomes

Vlado Perkovic, MD (Georgia Institute for Global Health, Sydney, Australia)

The safety data makes CANVAS a more complicated story. Dr. Vlado Perkovic presented these results, the headline being a near doubling of lower limb amputations with canagliflozin vs. placebo (HR=1.97, 95% CI: 1.41-2.75, p<0.001). In total, there were 187 lower limb amputations across the two outcomes trials (CANVAS and CANVAS-R), occurring at a rate of 6.3/1,000 patient-years in the canagliflozin arm vs. 3.4/1,000 patient-years in the placebo arm. Approximately 71% of these amputations occurred at the level of the toes or metatarsals, though some were above the ankle and a smaller number were above the knee. The Kaplan-Meier curves for lower-extremity amputations separate around ~year one and continue to diverge for six years post-randomization. Dr. Perkovic presented a multivariate analysis of common risk factors for amputation, which disappointingly showed consistently higher risk with canagliflozin vs. placebo, regardless of a patient’s prior history of amputation, peripheral vascular disease, etc. (see below for a breakdown of this data). While prior history of amputation leads to the greatest chance of a subsequent amputation, this risk is still intensified to the same degree by canagliflozin vs. placebo. Without any insight into what is mediating canagliflozin’s adverse impact on the lower limbs, most experts with whom we have spoken (admittedly still a small number) say that the risk appears to be associated with the molecule itself. This suggests that HCPs won’t be able to tailor prescriptions based on patient disposition (i.e. if the effect on lower limb amputations was driven by a particular subgroup. For example, if this risk were limited to participants with a risk like baseline peripheral vascular disease, this safety issue might be circumvented with a single black box warning not to prescribe Invokana to patients with peripheral vascular disease. At present, that does not appear to be the case. The FDA initiated an investigation of lower limb amputations based on interim CANVAS results in May 2016, and then just last month issued a boxed warning on all products in the Invokana family, so of course we knew this was likely to be an upsetting outcome regardless of the CV data.

• J&J now faces the very challenging task of promoting a favorable risk/benefit profile for its SGLT-2 inhibitor. Will patients risk a toe (or possibly lower limb) for the chance to prevent MI, stroke, and CV death with other in-class choices available? Will providers prescribe Invokana when there’s another SGLT-2 inhibitor with the same demonstrated risk reduction for three-point MACE and no signal for amputations? How will this all be reflected on formularies? We’ve heard mixed opinions from thought leaders so far: Some say they’ll keep patients on Invokana, while others advocate for switching to Jardiance. Some suggest (with hope!) that the lower limb amputation risk could be manageable if further investigations identify a confounding variable apart from the canagliflozin molecule itself – we do think it’s critical to separate out the confounders, like, for example, adjudication. Others are wary that this risk may apply to empagliflozin as well and the EMPA-REG OUTCOME trial just wasn’t long enough to pick up on it. We’re hopeful that this latter point isn’t the case, since the heightened amputation risk with canagliflozin vs. placebo appears early on, beginning at year one. We’ll be heartbroken if amputation risk comes to define the narrative surrounding first-in-class SGLT-2 inhibitor Invokana or the drug class more broadly, given demonstrated CV superiority and renal benefits. We can foresee a future, however, where busy HCPs steer clear of any product in this class because of concerns surrounding lower limb amputation. Or, perhaps this risk will hurt the Invokana business but will encourage patient switches to Jardiance or Farxiga (AZ’s dapagliflozin). We’ll be watching these trends closely. Bottom line: This is a major safety concern that can’t be ignored, nor would we expect it to be by providers, patients, payers, or regulatory agencies. Amputation is a particularly vivid diabetes complication for patients and in the public eye, and we expect J&J will have to be exceptionally thoughtful in how it proceeds. Dr. List suggested to us that this signal could shine a light on the importance of greater education on foot care for people with diabetes – we hope J&J will be a leader in expanding understanding/management of this complication. Currently, we don’t believe patients have much education at all about how to minimize this risk and in fact, perhaps key education could provide significantly more benefit.
• In a separate call with us, Dr. Robert Cuddihy (VP of Medical Affairs for Cardiovascular and Metabolism) underscored Janssen’s continued commitment to the Invokana franchise, and suggested that amputation risk could be managed with improved patient education on foot care and regular screening. As he pointed out, amputations didn’t appear out of nowhere, but were usually preceded by infection or another warning sign. Moreover, the patient population enrolled in CANVAS was particularly prone to this complication (with high CV risk corresponding to an elevated risk of lower-extremity amputations as well). In contrast, a metaanalysis of phase 3 canagliflozin studies found a much lower base rate of lower limb amputations in the background diabetes population vs. the high-risk diabetes population (0.6/1,000 patients vs. 2.4/1,000 patients, respectively). On the other hand, Dr. Cuddihy acknowledged that there’s something quite visceral about an amputation (vs. a heart attack) that may affect an individual patient’s decision on whether or not to start or continue Invokana treatment. Further post-hoc analyses of CANVAS and CANVAS-R will certainly provide more answers. Again, Dr. Cuddihy emphasized that J&J received the final data from these outcomes trials with little time remaining before ADA – continued analysis will come with more time.
• The hazard ratio for low-trauma bone fractures was 1.23 in favor of placebo, but this did not reach statistical significance (95% CI: 0.99-1.52). Fractures were another safety concern to watch out for in CANVAS and CANVAS-R, given the FDA’s strengthened label warning on this front, and it was reassuring to see no statistically significant signal across the two outcomes trials. Interestingly, there was a statistically significant increase in fracture risk in CANVAS (HR=1.55, 95% CI: 1.21-1.97) but not in CANVAS-R (HR=0.86, 95% CI: 0.62-1.19), and Dr. Perkovic reported a statistically significant p-value of 0.005 for this interaction. Further investigations will have to unpack this and determine how concerned patients/providers should be about canagliflozin and bone health. Said Dr. Neal, “I’m not easily persuaded by things happening by chance, but this is a weird result. We don’t see a fracture signal in EMPA-REG OUTCOME, nor in CANVAS-R, nor in any of the other CANVAS trials, so it’s possibly by chance.”
• As expected, genital mycotic infections were significantly more likely among females taking canagliflozin (HR=4.37, 95% CI: 2.78-6.88) and among males taking canagliflozin (HR=3.76, 95% CI: 2.91-4.86). DKA was another prespecified point-of-interest, but no statistically significant signal was detected. The DKA event rate was 0.6/1,000 patient-years in the canagliflozin group vs. 0.3/1,000 patient-years in the placebo group (HR=2.33, 95% CI: 0.76-7.17). Of 18 total cases of DKA, five patients were later found to have autoimmune/type 1 diabetes. In general, the concerns surrounding SGLT-2 inhibitors/DKA are more pronounced for a type 1 patient population, so this was a reassuring safety finding for canagliflozin as a type 2 diabetes therapy. That said, we continue to believe that SGLT-2 inhibitors could be advantageous for some patients with type 1, provided there is strong education on ketone monitoring and other DKA risk management.
• For all other adverse events, there was no significant difference in frequency between the canagliflozin and placebo arms. Serious adverse events occurred at a rate of 104/1,000 patient-years among canagliflozin-treated participants and 120/1,000 patient-years among placebo-treated participants (HR=0.93, 95% CI: 0.87-1.00). There were 1,025 total adverse events that led to study discontinuation – 35/1,000 patient-years vs. 33/1,000 patient-years in the canagliflozin and placebo groups, respectively (HR=1.13, 95% CI: 0.99-1.28). Hospitalization due to any cause occurred at a rate of 119/1,000 patient-years in the canagliflozin group vs. 131/1,000 patient-years in the placebo group (HR=0.94, 95% CI: 0.88-1.00). Data was also collected on UTIs, hypoglycemia, osmotic diuresis, volume depletion, severe hypersensitivity/cutaneous reaction, hepatic injury, venous thromboembolic events, photosensitivity, and acute pancreatitis, with no statistically significant difference in event rates between the canagliflozin and placebo groups.

Implications for Clinical Practice

David Matthews, DPhil (University of Oxford, UK)

To put the benefit-risk profile into perspective, Dr. David Matthews shared the expected incidence rate for a number of endpoints in the CANVAS program. For every 1000 patients treated with canagliflozin over five years, we can expect 23 fewer patients to experience a MACE event, 16 fewer patients to experience hospitalization for heart failure, and 17 fewer patients to experience the renal composite endpoint (renal death, renal replacement therapy, or 40% reduction in eGFR). In total, 56 fewer patients would be expected to experience on of these cardiovascular or renal events – this is especially notable considering that patients with diabetes face an excess residual cardiovascular risk and that few treatments are available for heart failure or diabetic nephropathy. On the other hand, these substantial wins would be expected to occur at the cost of 15 additional patients experiencing a lower-limb amputation (including 10 toe or forefoot amputations and five above-the-ankle amputations). For comparison, based on EMPA-REG OUTCOME, for every 1,000 patients treated over three years (a shorter time period than the CANVAS figures), clinicians can expect 22 fewer CV deaths, 25 fewer deaths overall, and 14 fewer hospitalizations for heart failure with empagliflozin therapy. The only strong safety signal observed in the trial was genital infections – treatment with empagliflozin in 1,000 patients would be expected to produce 53 additional genital infections over three years.

• Dr. Matthews highlighted the analysis presented earlier by Dr. Neal a lack of significant interaction between cardiovascular disease status at baseline and the CV benefit for canagliflozin. He emphasized that there’s no clear difference in outcome or size of the hazard ratios or confidence intervals when subgroups of those with and without CV disease are examined. That said, he also underscored that the study is not powered to distinguish between the primary and secondary prevention populations (we may have to wait until the much larger DECLARE trial (n=17,000) for a clearer understanding of this). Overall, Dr. Matthews stated that results hold for a patient population that matches the one in CANVAS, that is one third primary prevention and two thirds secondary prevention.
• Dr. Matthews also offered a direct comparison of primary and secondary endpoint hazard ratios and confidence intervals between CANVAS and EMPA-REG OUTCOME. While acknowledging the caveat that it’s extremely difficult to draw comparisons across trials due to differences in participant population, trial design, analytic approaches, and drug effects, Dr. Matthews nonetheless presented a helpful slide superimposing the key CANVAS hazard ratios and confidence intervals with that of EMPA-REG OUTCOME (see below). Overall, Dr. Matthews characterized the findings of the two trials as “effectively concordant” – indeed, it appears that the hazard ratios and confidence intervals between the two trials are generally very consistent. In fact, Dr. Matthews pointed out that the hazard ratios and confidence intervals for the primary MACE outcome in the two trials were almost identical. For comparison, the hazard ratio in the CANVAS program was 0.86 (95% CI: 0.75-0.97, p=0.0158 for superiority) and the hazard ratio in the EMPA-REG OUTCOME trial was also 0.86 (95% CI: 0.74-0.99, p<0.001 for non-inferiority, p=0.038 for superiority). Notably, the “nearly insignificant” p-value for the primary endpoint was a sticking point in the FDA Advisory Committee discussion on the Jardiance CV indication, so we’ll be curious to see how the FDA digests the CANVAS data for a label update. Additionally, the CV death component of MACE was not individually significant in CANVAS, whereas the risk of CV death was highly significantly reduced in EMPA-REG OUTCOME and the indication ultimately received for Jardiance was only for CV death. J&J management has already confirmed that the company will submit a Supplemental New Drug Application (sNDA) seeking an expanded indication to the FDA by the end of September – we’ll be following closely to see what kind of language this data will support from a regulatory standpoint (and in guidelines as well).
  
  • There also appears to be some heterogeneity in the non-fatal stroke results – while neither finding was significant, risk for non-fatal stroke trended toward reduction in CANVAS while there was actually signal for increased stroke in EMPA-REG OUTCOME. The confidence intervals for both were fairly wide and cross the line of unity in both trials, however, so we certainly don’t think any definitive comments can be made on the stroke effect of either drug or the class as a whole.

Independent Commentary

Clifford Bailey, MD (Aston University, Birmingham, UK)

In his independent commentary, Dr. Clifford Bailey put these integrated CANVAS/CANVAS-R results into context with EMPA-REG OUTCOME for Lilly/BI’s SGLT-2 inhibitor Jardiance (empagliflozin). He posited that CV and renal benefits are highly likely to be class effects for SGLT-2 inhibitors, based on the parallel data in CANVAS and EMPA-REG OUTCOME. The risk reduction for three-point MACE is exactly the same in both trials (14%). Canagliflozin demonstrated a 33% risk reduction for heart failure hospitalization, while empagliflozin demonstrated a 35% risk reduction for this endpoint (p=0.002 vs. placebo). Empagliflozin also significantly reduced risk for diabetic nephropathy by 39%, in comparison to canagliflozin’s 27% risk reduction for progression to albuminuria and 40% risk reduction for the composite endpoint of renal death, renal replacement therapy, or 40% reduction in eGFR. Dr. Bailey mentioned CVD-REAL, the AZ-sponsored real-world analysis that found a significant 39% risk reduction for heart failure hospitalization associated with SGLT-2 inhibitors (including Invokana, Jardiance, and Farxiga) vs. other glucose-lowering drugs (p<0.001). He suggested that all signs so far point to a cardioprotective class effect for SGLT-2 inhibitors, with especially strong signals for a heart failure benefit (though this will have to be determined through RCTs, such as Lilly/BI’s EMPEROR HF program and AZ’s Dapa-HF program). One of the clear bright spots of this new CVOT data is reassurance that EMPA-REG OUTCOME results were not a fluke. For now, these integrated results have created a complicated risk/benefit profile for Invokana, and Dr. Bailey emphasized that the near doubling of risk for lower-extremity amputations is a very real safety concern. Some have said the biggest win from CANVAS may actually manifest for the Jardiance franchise, since empagliflozin’s CV benefits now have more credence without any associated amputation risk – obviously, we would not imagine that anyone would see the troubling safety data as a win for any manufacturer or any patients.

• Dr. Bailey drew attention to the different patient populations in CANVAS and EMPA-REG OUTCOME. Whereas 99% of EMPA-REG OUTCOME participants has established CV disease at baseline or were at very high CV risk, CANVAS enrolled a much lower proportion of high-risk individuals, only 65%. “The 65% is much more reminiscent of the population you’d see in routine practice,” Dr. Bailey explained, which highlights another important contribution of CANVAS to our understanding of SGLT-2 inhibitors. He argued that the positive CV effects of this therapy class may apply in primary as well as secondary prevention. If this primary cardioprotection is confirmed further by AZ’s CVOT DECLARE, which also enrolls a large subset of lower-risk participants, it could be truly transformative for diabetes care – we could give patients a glucose-lowering, weight-lowering, convenient oral medication that protects stroke, heart attacks, and CV death early on.
• That the hazard ratio for stroke trended in the right direction in CANVAS is also reassuring, Dr. Bailey suggested. In EMPA-REG OUTCOME, strokes were actually more common in the treatment vs. placebo arm, though the 1.24 hazard ratio did not reach statistical significance (95% CI: 0.92-1.67, p=0.16). In a separate conversation with our team, Dr. Neal suggested that Lilly/BI may have been “unlucky” on this stroke endpoint. Ideally, further investigations of mechanism help elucidate differential effects of canagliflozin and empagliflozin on non-fatal MI, non-fatal stroke, and CV death. For now, we hope the focus remains on the significant risk reduction for three-point MACE and CV events in general. Janssen’s Dr. List announced that a Supplemental New Drug Application (sNDA) for inclusion of the canagliflozin CV data on the Invokana label will be submitted to the FDA by the end of September.

Close Concerns Questions

Q: What are the risk factors for amputation? Are there clear patient populations that should avoid Invokana?

Q: What are the logical next steps to investigate amputation risk using data from databases used in the CVD-REAL study or comparable datasets such as those used by major US insurance companies? Since Invokana has been out the longest, what is the best way to compare compounds?

Q: What is the best way to interpret the different adjudication approaches of amputations used in various CVOTs?

Q: To what extent might the amputation risk be a class effect?

Q: How much will J&J continue to invest in the Invokana franchise? There has previously been discussion of a prediabetes CVOT for the drug, as well as the potential for a phase 3 obesity program for the combination of canagliflozin and phentermine.

Q: What’s going to happen to prescribing habits? Is there a reason an HCP might still prescribe Invokana over Jardiance beyond formulary and how would typical clinicians trade off better glycemic or weight advantages associated (at least for some patients) with the relatively higher amputation risk (despite low overall numbers)? Will the amputation risk is going to deter HCPs from Invokana, specifically, or perhaps from the whole SGLT-2 class? How much more

Q: How will these results impact formularies?

Q: How will patients and providers and professional groups view the trade-off between lowering CV events and increasing chances of a lower limb amputation?

Q: How does the “do no harm” tenet for healthcare providers play into decisions around drugs to use in this class?

Q: What concerns exist over patients enrolled in CANVAS-R who may be at higher than typical risk of amputations?

Q: What components of outcomes trials should be changed to make them more comparable? Would it be a useful investment to have an outcome trial with all SGLTs?

Oral Presentations: ADA Presidents Oral Session

Hospitalization for Heart Failure and Death in New Users of SGLT2 Inhibitors in Patients With and Without Cardiovascular Disease—CVD-REAL Study

Matthew Cavender, MD (University of North Carolina, Chapel Hill, NC)

Dr. Matthew Cavender shared new findings from the AZ-sponsored CVD-REAL study, showing consistent CV benefits to SGLT-2 inhibitor therapy across primary and secondary prevention populations. Approximately 87% of registered participants (n=306,156) had no prior history of CV disease at baseline, as we learned at ACC 2017 during the initial results presentation, and these individuals still experienced an impressive 46% relative risk reduction for all-cause mortality with an SGLT-2 inhibitor (n=133,549) vs. another glucose-lowering drug (n=133,294) such as metformin (most common), sulfonylureas, DPP-4 inhibitors, TZDs, GLP-1 agonists, or insulin (HR=0.54, 95% CI: 0.44-0.66). Patients with established CV disease experienced a 53% relative risk reduction for all-cause death with an SGLT-2 inhibitor (HR=0.47, 95% CI: 0.36-0.61) – as expected, the absolute risk reduction is greater because this high-risk subset had a larger total number of events. Dr. Cavender reminded everyone that the risk reduction for all-cause mortality was 51% across the entire study (p<0.001), which falls between 46% for a primary prevention cohort and 53% for a secondary prevention cohort. Initiation of SGLT-2 inhibitor therapy lowered a high-risk patient’s risk for heart failure hospitalization by 31% (HR=0.69, 95% CI: 0.59-0.8) and a low-risk patient’s risk for this endpoint by 55% (HR=0.45, 95% CI: 0.32-0.63), compared to a 39% relative risk reduction across CVD-REAL in its entirety (p<0.001). For the composite endpoint of hospitalization for heart failure/death from any cause, SGLT-2 inhibitors reduced risk for the primary prevention group by 41% (HR=0.59, 95% CI: 0.52-0.67) and for the secondary prevention group by 48% (HR=0.52, 95% CI: 0.44-0.61), compared to a 46% relative risk reduction across the whole trial (p<0.001). It’s unclear why lower-risk participants experienced even greater absolute risk reductions for heart failure hospitalization and the composite endpoint vs. patients with a history of CV events – it’s possible that SGLT-2 inhibitors may exert a preventive or protective effect against heart failure in relatively more healthy hearts, though of course this is speculation since the mechanism of benefit is still largely a mystery. All in all, this data suggests a broad CV benefit to SGLT-2 inhibitors. There was not information shared on amputations but we will be eager to learn anything on this front, as well as on fractures.

• Dr. Cavender emphasized the real-world nature of this investigation. While there are limitations to observational research, CVD-REAL also translates findings from EMPA-REG OUTCOME into real clinical settings – and in an enormous population. “It gives us some degree of confidence that data from randomized controlled trials (RCTs) like EMPA-REG OUTCOME has to do with how drugs are playing out in real-world clinical practice,” he explained. We agree that there’s excitement in this real-world dataset showing profound CV benefits for the SGLT-2 class, including Lilly/BI’s Jardiance (empagliflozin), J&J’s Invokana (canagliflozin), and AZ’s Farxiga (dapagliflozin), even if they are slightly inflated. We’ve heard from many thought leaders, including CVOT expert Dr. Silvio Inzucchi and Dr. Matthew Riddle at this very meeting, that demonstrating primary CV prevention is the next frontier for SGLT-2 inhibitors. CVD-REAL offers a big hint for a primary cardioprotective class effect, one that will hopefully be confirmed by ongoing RCTs and post-hoc analyses of completed RCTs. The CANVAS CVOT for Invokana, presented yesterday, showed 14% relative risk reduction for three-point MACE (p=0.02 for superiority vs. placebo) and the participant population included about ~1/3 participants without established CV disease at baseline. AZ’s DECLARE trial will feature an even larger primary prevention cohort, and is expected to complete in April 2019.

Oral Presentations: GLP-1s and SGLT2s—To Do or Not to Do in Type 1 Diabetes Mellitus?

Twenty-Four-Week Efficacy and Safety of Sotagliflozin, a Dual SGLT1 and SGLT2 Inhibitor, as Adjunct Therapy to Insulin in Type 1 Diabetes (inTandem1)

John Buse, MD, PhD (University of North Caroline, Chapel Hill, NC)

UNC’s Dr. John Buse presented full data from the phase 3 inTandem1 trial, elucidating the benefit-risk profile of SGLT-1/2 dual inhibitor sotagliflozin in type 1 diabetes. inTandem1 was a double-blinded trial that randomized 793 patients to either placebo, sotagliflozin 200 mg, or sotagliflozin 400 mg. The trial included a six-week insulin optimization period prior to randomization. As was reported in the topline results, even in the context of optimized insulin, the trial impressively met its primary endpoint by producing a mean placebo-adjusted A1c reduction of 0.35% in the 200 mg arm (baseline A1c post-optimization=7.6%; p<0.001) and 0.41% in the 400 mg arm (baseline A1c post-optimization=7.6%; p<0.001) at 24 weeks. inTandem1 employed a hierarchical statistical testing structure, in which secondary endpoints were assessed in the following order: (i) “net benefit” (defined as target A1c<7% with no severe hypoglycemia or DKA); (ii) weight; (iii) bolus insulin dose; (iv) fasting plasma glucose (FPG); and two measures of patient-reported outcomes – (v) the Diabetes Treatment Satisfaction Questionnaire status (DTSQ) score; and (vi) the two-item Diabetes Distress Screening Scale (DDS2) questionnaire score. We previously learned from a second release of topline data from inTandem1 that the 400 mg dose demonstrated superiority to placebo for all of these secondary endpoints, while the 200 mg dose only demonstrated superiority for A1c, net benefit, and weight. Dr. Buse very excitingly provided new detail on these secondary outcomes. More than twice as many patients achieved net benefit on sotagliflozin 400 mg compared to placebo: 44% of participants in the 400 mg arm achieved “net benefit” at week 24, compared to just 22% of those in the placebo arm (p<0.001). Those in the 200 mg arm also substantially more likely to achieve net benefit – 34% (p=0.002 vs. placebo). As was shared in the topline results, patients taking sotagliflozin experienced a 1.6 kg (3.5 lbs) and a 2.7 kg (6 lbs) weight reduction at 24 weeks with the 200 mg and 400 mg doses, respectively – this compares to a mean weight gain of 0.8 kg (1.8 lbs) in the placebo group (p<0.001). The results shared today revealed that the superiority of sotagliflozin 400 mg for the other secondary endpoints was similarly highly statistically significant (p<0.001). On the other hand, Dr. Buse noted that there was some heterogeneity between the impact of the two doses on bolus insulin dose – while sotagliflozin 400 mg was associated with a statistically significant decrease in bolus insulin (p<0.001; exact dosages not shared), there was no statistically significant difference in bolus insulin dose among those treated with sotagliflozin 200 mg and those in the placebo arm. On the other hand, the p-value for the difference between the 200 mg arm vs. placebo was below 0.05 for FPG (p=0.036), DTSQ score (p<0.001), and DDS2 score (p=0.002). That said, because of the hierarchical nature of the statistical testing, Dr. Buse emphasized that these findings may only be characterized as “descriptive” rather than significant. While some more conservative clinical trial purists may make a big deal about this, we’re very, very pleased to see consistency between the 400 mg and the 200 mg dose for these very critical endpoints. We’re especially excited about the quantification of the quality of life and patient satisfaction benefits of this drug – anecdotally, we’ve heard rave review from patients with type 1 diabetes taking selective SGLT-2 inhibitors and we’re glad to see this backed up with hard data. Safety data was as reported in the topline results, with fairly balanced adverse event rates across all three arms, somewhat higher rates of DKA with sotagliflozin, and somewhat lower rates of severe hypoglycemia. While there is some concern in some quarters about type 1 patients taking this class, we don’t think there is a way to stop it – it may be valuable to look at gaps in therapy for type 1s in order to better understand patients taking SGLT-2s off label. We applaud Lexicon for collecting so many outcomes and hope that these will be standardized soon. 

inTandem1 Primary and Secondary Efficacy Endpoint Results

Endpoints	Sotagliflozin 200 mg (p-value vs. placebo)	Sotagliflozin 400 mg (p-value vs. placebo)	Placebo
A1c	-0.43% (p<0.001)	-0.49% (p<0.001)	-0.08%
Net Benefit (proportion of patients with A1c<7% and no severe hypoglycemia or DKA)	34% (p=0.002)	44% (p<0.001)	22%
Weight	1.6 kg (3.5 lbs, p<0.001)	2.7 kg (6 lbs, p<0.001)	0.8 kg (1.8 lbs)
Bolus insulin	Undisclosed (p=0.10)	Undisclosed	Undisclosed
Fasting plasma glucose (FPG)	Undisclosed (p=0.036)	Undisclosed (p<0.001)	Undisclosed
Patient-reported Diabetes Treatment Satisfaction Questionnaire status (DTSQ) score	Undisclosed (p<0.001)	Undisclosed (p<0.001)	Undisclosed
Patient-reported Diabetes Distress Screening Scale (DDS2) score	Undisclosed (p=0.002)	Undisclosed (p<0.001)	Undisclosed

inTandem1 Safety Results

	Sotagliflozin 200 mg	Sotagliflozin 400 mg	Placebo
Proportion of patients with ≥1 treatment-emergent adverse events	67%	71%	68%
% patients with diarrhea	7%	10%	7%
% patients with genital mycotic infection	6%	10%	3%
Number of patients with DKA	3 (1.1%)	8 (3.1%)	0
Number with severe hypoglycemia	11 (4.2%)	12 (4.6%)	18 (6.7%)

A 12-Week Dose-Ranging Study of Sotagliflozin, a Dual SGLT-1 and SGLT-2 Inhibitor, as Adjunct Therapy to Insulin in Type 1 Diabetes (inTandem4)

Paul Strumph, MD (Lexicon Pharmaceuticals, The Woodlands, TX)

Lexicon VP of Clinical Development Dr. Paul Strumph also took to the stage to discuss full results from the phase 2 dose-ranging inTandem4 study of sotagliflozin. The double-blinded, 12-week trial randomized 141 patients with type 1 diabetes to three doses of sotagliflozin (75 mg, 200 mg, or 400 mg), plus placebo. Unlike the phase 3 inTandem1 trial, inTandem4 only included a two-week placebo run-in period, rather than a six-week insulin optimization period.  The vast majority of the numeric data was already shared in the topline results, though Lexicon shared p-values for the first time, demonstrating that these results were highly statistically significant. The primary endpoint A1c results as well as the secondary urinary glucose excretion, postprandial glucose, body weight, fasting plasma glucose (non-inferior), and blood pressure results are summarized in the table below. Very notably, however, Lexicon shared data on beta-hydroxybutyrate (BHB) levels at baseline and at week 12 – as a measure of ketogenesis, BHB measurements are very helpful as we consider the potential DKA risk of sotagliflozin. Notably, the mean increase in blood BHB at week 12 was only 0.1 mmol/l, which is the lowest value detectable by a point of care BHB meter. Dr. Strumph also noted that this level of BHB increase is lower than what is typically seen with selective-SGLT-2 inhibitors. Overall incidence of DKA was very low this trial, with the only case of DKA in the entire trial occurred in the 400 mg arm – though, very notably, the patient who experienced DKA chose to continue the study after the event, demonstrating that the perceived benefits outweighed the DKA risk for this patient. Although just one case, this is unsurprising to us. The level of DKA observed in both inTandem4 and inTandem1 is somewhat lower in all arms than might be expected in a general type 1 diabetes population. Dr. Buse noted during Q&A following the inTandem1 presentation that all participants in the trial were very carefully and intensively educated on DKA risk management. Our sense is that this level of intensive education rarely happens in the “real-world,” and we hope that Lexicon will continue its leadership in pairing sotagliflozin with appropriate educational efforts when the product launches. Write Richard Wood of dQ&A for more on overall level of understanding by patients of DKA and DKA risk.

inTandem4 Primary and Secondary Efficacy Endpoint Results

Endpoints (placebo-adjusted for all efficacy endpoints)	Sotagliflozin 75 mg (p-value vs. placebo)	Sotagliflozin 200 mg (p-value vs. placebo)	Sotagliflozin 400 mg (p-value vs. placebo)
A1c	-0.25% (p=0.07)	-0.48% (p<0.001)	0.38% (p=0.006)
Urinary glucose excretion (g/day)	42 (p=0.006)	58 (p<0.001)	70 (p<0.001)
Change in 2-hour postprandial glucose reduction (mg/dl)	-20 (p=0.27)	-27 (p=0.15)	-49 (p=0.006)
Body weight	-1.3 kg (2.9 lbs; p=0.38)	-2.4 kg (5.3 lbs; p<0.001)	-2.8 kg (6.2 lbs; p<0.001)
Change in fasting plasma glucose (mg/dl)	-9 (p=0.51)	-9 (p=0.48)	-21 (p=0.10)
Change in systolic blood pressure (mmHg) in subgroup of patients with baseline ≥130 mmHg	-8.4 (p=0.26)	-6.8 (p=0.28)	-14.3 (p=0.013)

inTandem4 Safety Results

	Sotagliflozin 75 mg	Sotagliflozin 200 mg	Sotagliflozin 400 mg	Placebo
Proportion of patients with ≥1 treatment-emergent adverse events	48.6%	28.6%	34.3%	50%
Number of patients with diarrhea	0	1	1	0
Number with genital mycotic infection	1	1	1	0
Number with DKA	0	0	1 (2.9%)	0
Number with severe hypoglycemia	1 (2.9%)	1 (2.9%)	1 (2.9%)	0

Oral Presentations: Landscape of Therapeutic Trials in Type 2 Diabetes

Safety and Efficacy of Ertugliflozin Plus Sitagliptin vs. Either Treatment Alone after 52 Weeks in Subjects with T2DM Inadequately Controlled on Metformin: VERTIS FACTORIAL Trial Extension

Richard Pratley, MD (Florida Diabetes and Endocrine Center, Orlando, FL)

Dr. Richard Pratley shared one-year findings from the VERTIS FACTORIAL trial, underscoring the glucose-lowering and weight loss efficacy of Merck/Pfizer’s SGLT-2 inhibitor ertugliflozin in combination with sitagliptin (Merck’s DPP-4 inhibitor Januvia). This is particularly exciting as we await FDA decisions on ertugliflozin, ertugliflozin/metformin (fixed-dose combination), and ertugliflozin/sitagliptin (fixed-dose combination) expected by January 2018 – we’ve been looking forward to this data for a long time! In VERTIS FACTORIAL, 1,233 patients with type 2 diabetes on stable metformin therapy were randomized to one of five arms: (i) a 5 mg dose of ertugliflozin, (ii) a 15 mg dose of ertugliflozin, (iii) a 100 mg dose of sitagliptin, (iv) a combination regimen of 5 mg ertugliflozin/100 mg sitagliptin, or (v) a combination regimen of 15 mg ertugliflozin/100 mg sitagliptin. Initial 26-week results were presented in a poster at EASD 2016, and Dr. Pratley discussed data from the trial extension out to 52 weeks, which demonstrated sustained superior reductions in A1c and fasting plasma glucose for the SGLT-2/DPP-4 combinations vs. either agent alone. After one year of treatment, A1c dropped by 1.4% from a baseline 8.6% for both the combo therapy groups vs. an A1c decline of 1%, 0.9%, and 0.8% for the 5 mg ertugliflozin, 15 mg ertugliflozin, and 100 mg sitagliptin groups, respectively (and that’s in an RCT – unlikely that would be seen in “real life” from our admittedly speculative view). In both combo arms, 40% of participants reached an A1c goal of <7% after one year vs. 26% of patients on 5 mg ertugliflozin, 23% of patients on 15 mg ertugliflozin, and 27% of patients on sitagliptin. A “global” word on findings such as these – we’d love to see what the A1c goals would look like with other interventions combined after the initial findings (diet, exercise, behavior modification, peer to peer counseling, etc.)

• Ertugliflozin also demonstrated a profound weight loss benefit in VERTIS FACTORIAL. Dr. Pratley showed that ertugliflozin was associated with 2.4 kg (5.3 lbs) weight loss at a 5 mg dose, 3.2 kg (7.1 lbs) weight loss at a 15 mg dose, 2.4 kg (5.3 lbs) weight loss at a 5 mg dose in combination with sitagliptin, and 2.8 kg (6.2 lbs) weight loss at a 15 mg dose in combination with sitagliptin. Meanwhile, patients on sitagliptin alone in VERTIS FACTORIAL experienced 0.1 kg (0.22 lbs) weight loss on average over the course of a full year. Baseline body weight was 87 kg-89 kg (192 lbs-196 lbs) across all study arms. Weight loss is one of the key aspects to SGLT-2 inhibitors that makes these products so appealing for type 2 diabetes patients (not to mention the superior A1c-lowering and possible CV benefits). We’re not at all surprised to see marked improvements in body weight with ertugliflozin treatment vs. sitagliptin or placebo, but we’re always happy to see corroborating evidence on this front. We’re also pleased to see that combination with sitagliptin does not appear to substantially attenuate the weight loss effect of ertugliflozin.
• Dr. Pratley’s presentation highlighted SGLT-2/DPP-4 fixed-dose combination tablets as an important advancement in type 2 diabetes care. He began with the statement that SGLT-2 inhibitors and DPP-4 inhibitors have complementary mechanisms of action, which suggests that a combination of the two could be a more efficient way to get patients to goal – especially those with high baseline A1c. VERTIS FACTORIAL provides hard evidence for the benefits to this particular combination vs. either monotherapy, with more patients getting to A1c goal while also losing weight and facing a lower pill burden.

Safety and Efficacy of Ertugliflozin after 52 Weeks in Subjects with T2DM Inadequately Controlled on Metformin and Sitagliptin: Results from the Extension Phase of the VERTIS SITA2 Trial

Jie Liu, MD (Merck & Co., Chicago, IL)

Dr. Liu presented 52-week results from VERTIS SITA2 investigating ertugliflozin as an add-on to a metformin/sitagliptin regimen – a follow-up to the 26-week data shared in an oral presentation at EASD 2016. Participants (n=464) with type 2 diabetes experienced a mean 0.8% A1c decline from a baseline of 8.1% with 5 mg ertugliflozin after one year, while patients in the placebo arm showed essentially flat A1c from baseline 8%. Similarly, people randomized to 15 mg ertugliflozin experienced a mean 0.8% A1c reduction from a baseline of 8%. Dr. Liu displayed graphs to clearly depict this sustained glucose-lowering effect out to one year, which is certainly compelling, in our view. In VERTIS SITA2, 33% of patients on ertugliflozin reached an A1c target <7% at week 52, regardless of dose, compared to only 14% of the placebo group. We’re glad to see such strong data from the VERTIS program, and we’re excited by the prospect of a fourth SGLT-2 inhibitor coming soon to the commercial market by a group that could more successfully get this class to the patients that need it. Expanded options within this class will be a noteworthy win, and we look forward to seeing how ertugliflozin may grow whole class sales – while patients and clinicians in the US are rarely “choosing” compounds anymore, as much as the formularies are making choices for them, we do believe that a powerhouse combo of Merck/Pfizer marketing in this class would be positive for all.

• Weight loss effects were consistent between week 26 and week 52 in VERTIS SITA2. According to Dr. Liu, body weight decreased by a mean 3.5 kg (7.7 lbs) from a baseline 88 kg (194 lbs) for the 5 mg ertugliflozin group, by a mean 2.8 kg (6.2 lbs) from a baseline 87 kg (192 lbs) the 15 mg ertugliflozin group, and by 1 kg (2.2 lbs) from a baseline 87 kg (192 lbs) for the placebo group.
• As Dr. Liu put it, DPP-4 inhibitors are already commonly considered as a second-line therapy option after metformin. He suggested that this data supports earlier intervention with an SGLT-2 inhibitor alongside. Merck’s Januvia (sitagliptin) leads the DPP-4 inhibitor class in sales and has surely cultivated familiarity among diabetes care providers, so we’re hopeful that a fixed-dose combination of ertugliflozin/sitagliptin – if approved – also becomes an early consideration for type 2 diabetes treatment. That said, frustratingly in the US, clinicians and payers seem to be less comfortable with fixed dose combinations than do their counterparts in other geographic regions. We’d love to get more patient sentiments, particularly that relate to adherence, to the payers.

The Long-Term Efficacy and Safety of Canagliflozin in Combination with Insulin in Japanese Patients with T2DM

Shinichi Harashima, MD (Kyoto University, Japan)

Dr. Shinichi Harashima presented results from a one-year study of SGLT-2 inhibitor canagliflozin (n=76) vs. placebo (n=70) added onto a background of insulin therapy. Canagliflozin, branded by Mitsubishi Tanabe Pharma as Canaglu in Japan (and branded by J&J as Invokana ex-Japan), was associated with superior A1c reductions vs. placebo for type 2 diabetes patients on premixed, basal only, or basal-bolus therapy at baseline (p<0.001 for all comparisons). After 16 weeks, the A1c treatment difference between the two study arms was 1.1% (p<0.001). All participants then entered a 36-week open label period, and patients switched from placebo onto canagliflozin achieved similar levels of A1c decline by week 52. The SGLT-2 inhibitor was also associated with superior reductions in fasting plasma glucose, body weight, and HOMA2-%B, which reflects beta cell function (p<0.001 vs. placebo for all comparisons). While hypoglycemia rates were similar across the two study arms – 4.85 events per subject-year of exposure vs. 4.51 events per subject-year of exposure with canagliflozin vs. placebo, respectively – patients on canagliflozin who experienced a meaningful reduction in daily insulin dose did face substantially lower risk for hypoglycemia. Dr. Harashima reported that mean daily insulin dose for the 19 patients experiencing >8 hypoglycemia episodes over the course of the trial was 35.7 units, compared to only 27.4 units for the 72 patients who experienced no hypoglycemia events during the trial. The implication here is that a larger, longer study might show a beneficial effect of canagliflozin therapy on hypoglycemia risk, mediated by a change in daily insulin requirements. We’d love to see that data.

Oral Presentations: Translating Therapeutics to the Real World

Dapagliflozin in Renal Impairment: The Association of British Clinical Diabetologists Nationwide Dapagliflozin Audit

Robert Ryder, MD (City Hospital, Birmingham, UK)

Dr. Robert Ryder presented data from the UK’s Association of British Clinical Diabetologists (ABCD) nationwide audit, demonstrating the efficacy of dapagliflozin in type 2 diabetes patients with normal, mild, and moderate renal impairment. The ABCD audit collected anonymous data of real type 2 diabetes patients (baseline A1c of ~9.5%; disease duration of 8.2 to 11 years) treated with dapagliflozin between 2014 and 2016 (n=2,027). The patients were categorized into three groups, depending on baseline eGFR: CKD group 1 (normal, eGFR > 90 ml/min), group 2 (mild renal impairment, eGFR 60-90 ml/min), and group 3 (moderate renal impairment, eGFR 30-59ml/min). Study results found that the drug reduced A1c, weight, BMI, systolic blood pressure, and ALT by similar statistically and clinically significant amounts in normal and mild renal impairment. In moderate renal impairment, there was a reduction in weight and ALT but there was no significant impact on A1c or systolic blood pressure. Specifically, over approximately four months, comparing groups, mean A1c fell by 1.1 ± 1.1% from 9.7±1.4 to 8.6±1.5% (p=0.000) in group 1, 0.9±1.4% from 9.4±1.5 to 8.5±1.4% (p<0.001) in group 2, but did not change significantly in group 3 (9.3±1.4 to 9.1±1.8% [p=0.510]). Weight fell by 3.2±5.2 kg from 106.8±22.1 to 103.5±22.0 (p<0.001) in group 1, 2.1±4.8 kg from 101.1±22.4 to 99.0±22.0kg (p<0.001) in group 2 and 3.5±7.7kg from 105.9±18.3 to 102.4±18.1kg (p=0.003) in group 3. These data are reassuring in the versatility of SGLT-2 inhibitors’ benefits and also add to the conversation on how clinicians can better personalize therapies with regard to their patients’ comorbidities.

Questions and Answers

Q: I know that in the UK, they can stop medications after a couple of years. What criteria did you use to measure the stopping and restarting of medications?

A: There aren’t any particular criteria. Clinicians do whatever clinicians do. Some will stop if the med doesn’t work; others will continue. There isn’t any specific thing driving this for people. They do whatever they think is best for their patient.

Q: Was there a difference across side effect profiles?

A: The side effects were similar across groups.

Posters

DURATION-8 Randomized Controlled Trial 1-Year Results: Efficacy and Safety of Once-Weekly Exenatide (ExQW) Plus Once-Daily Dapagliflozin (DAPA) vs. ExQW or DAPA Alone (141-LB)

C Guja, J Frias, A Ahmed, E Hardy, H Wang, P Ohman, and S Jabbour

AZ presented new one-year DURATION-8 results, demonstrating that the combination of AZ’s SGLT-2 inhibitor Farxiga (dapagliflozin) and once-weekly GLP-1 agonist Bydureon (exenatide) maintained improvements in glycemic control, body weight, and SBP compared to either drug alone. These results represent the 24-week extension from the promising 28-week DURATION-8 results presented at this past EASD meeting. In this double-blind, multicenter study, adults with type 2 diabetes were randomized to either exenatide plus dapagliflozin, exenatide alone, or dapagliflozin alone. Of the initial 695 patients randomized, 564 (81%) completed the full 52-week treatment period. The findings demonstrated that at week 52, the combination therapy group continued to achieve greater reductions in A1c, FPG, 2-hour PPG, body weight, and SBP compared to either treatment group alone. Specifically, the -1.8% A1c reduction for exenatide/dapagliflozin dual therapy significantly exceeded those of exenatide (-1.4%; p<0.01) and dapagliflozin (-1.2%; p<0.01) alone. Notably, Body weight reductions were -3.3 kg for the dual therapy arm, significantly greater than -1.5 kg for exenatide monotherapy (p<0.001) and -2.3 kg for dapagliflozin monotherapy (p<0.001). SBP reductions were 4.5 mmHg, 0.7 mmHg (p<0.001), and 2.7 mmHg, respectively. Regarding safety and tolerability, the combination therapy was well tolerated, with slightly more adverse events vs. either drug alone (66.2% vs. 62.2% [exenatide] and 61.8% [dapagliflozin]), though the three groups had comparable rates of serious adverse events. In general, patients treated with exenatide unsurprisingly reported more GI adverse events. These results confirm the promising findings that made waves at last EASD and the excitement surrounding the GLP-1/SGLT-2 combination approach. As both of these classes have the potential for CV risk reduction, we would be interested to see if a combination therapy could provide further additive benefits. For more on DURATION-8 and AZ’s latest, please see our EASD 2016 and 1Q17 coverage.

24-Week Efficacy and Safety of Sotagliflozin, a Dual SGLT-1 and SGLT-2 Inhibitor, as Adjunct Therapy to Insulin in Type 1 Diabetes (inTandem2) (146-LB)

T Danne, B Cariou, P Banks, S Sawhney, P Strumph, and The Sotagliflozin inTandem2 Writing Group

The inTandem2 study demonstrated significant A1c reductions of 0.36% (200 mg dose) and 0.35% (400 mg dose) with sotagliflozin vs. placebo (p<0.001) in patients with type 1 diabetes on optimized insulin regimens (baseline A1c = 7.7-7.8% after insulin optimization). The company reported topline results from the study in December. The double-blind trial randomized 782 patients with type 2 diabetes to receive either placebo, 200 mg sotagliflozin, or 400 mg sotagliflozin for 24 weeks in addition to optimized insulin therapy. The study also included a double-blind long-term extension period of 24 weeks that is ongoing. In addition to the primary endpoint of A1c reduction at 24 weeks, investigators assessed a secondary endpoint of “net benefit”: the percentage of patients with A1c <7% at 24 weeks and no episodes of severe hypoglycemia or DKA during the study period. This endpoint was achieved by 32% of patients in both sotagliflozin groups vs. 15% of patients in the placebo group (p<0.001). While we appreciate seeing composite endpoints like these included in trials, as they are often more clinically relevant than A1c reductions alone, we understand from a regulatory perspective, there may need to be work standardizing them. In this case, while the significant difference vs. placebo is encouraging, the fact that less than a third of treated patients achieved the net benefit goal is somewhat disappointing. As for specific safety endpoints, rates of severe hypoglycemia were 3.8% with 200 mg sotagliflozin, 2.3% with 400 mg sotagliflozin, and 2.7% with placebo. DKA rates were 0.4% with 200 mg sotagliflozin, 1.1% with 400 mg sotagliflozin, and 0% with placebo.

12-Week Efficacy and Safety of Sotagliflozin, a Dual SGLT-1 and SGLT-2 Inhibitor, as Adjunct Therapy to Insulin in Young Adults with Poorly Controlled Type 1 Diabetes (JDRF Study) (147-LB)

B Bode, P Banks, S Sawhney, P Strumph, and The Sotagliflozin JDRF Study Writing Group

The JDRF-partnered study of sotagliflozin in young adults with poorly controlled type 1 diabetes failed to demonstrate significant A1c reductions vs. placebo but showed promising improvements in other clinically relevant endpoints. Lexicon announced topline results from the study in December. The trial enrolled 87 patients age 18-30 with type 1 diabetes and an A1c ≥9%. Patients were randomized to receive either 400 mg sotagliflozin or placebo for 12 weeks in addition to insulin; the primary endpoint was change in A1c at 12 weeks. Sotagliflozin produced placebo-adjusted A1c reductions of 0.35% (baseline = 9.7-9.9%) and the difference between groups was not statistically significant (p=0.10). Because the primary endpoint was not significant, p-values for secondary endpoints could not be used to declare statistical significance. However, sotagliflozin did appear to produce improvements vs. placebo on postprandial glucose, body weight, time in range, and A1c in patients with a baseline A1c of 9-10%. In addition, approximately 8 times as many patients in the sotagliflozin group achieved the “net benefit” endpoint of A1c <7% at 12 weeks with no severe hypoglycemia or DKA compared to the placebo group, though the absolute percentage of responders was low in both groups (16% vs. 2%). We were especially impressed by the CGM data from the study – sotagliflozin therapy produced a one-third increase in time spent in range of 70 mg/dl-180 mg/dl. This study is a good example of the limitations of using A1c as the sole metric of efficacy for diabetes drugs, as other parameters like time in range and weight loss are likely more relevant for many patients. While there is almost exclusive focus on A1c at the regulatory level (though JDRF and The diaTribe Foundation among others are actively advocating for regulatory consideration of outcomes beyond A1c), it’s important to note that this was a phase 2, non-pivotal trial in an extremely challenging population. See our discussion of the topline results for more of our thoughts on this study.

Effect of Ertugliflozin on Glycemic Control, Body Weight, Blood Pressure, and Bone Mineral Density in Type 2 Diabetes Mellitus Inadequately Controlled with Metformin Monotherapy: VERTIS MET Trial (1168-P)

J Rosenstock, J Frias, D Páil, B Charbonnel, R Pascu, D Saur, A Darekar, S Huyck, H Shi, B Lauring, and S Terra

In VERTIS MET, Merck/Pfizer’s SGLT-2 inhibitor candidate ertugliflozin showed superior lowering of A1c, fasting plasma glucose, body weight, and blood pressure vs. placebo. The study enrolled 621 patients with type 2 diabetes and a mean baseline A1c of 8%, randomizing them to ertugliflozin 5 mg, ertugliflozin 15 mg, or placebo. After 26 weeks, participants in the 5 mg ertugliflozin arm experienced a mean A1c treatment difference of 0.7% (p<0.001 vs. placebo), while those in the 15 mg ertugliflozin arm experienced a mean A1c treatment difference of 0.88% (p<0.001 vs. placebo). Body weight dropped similarly, although these reductions were not dose dependent, meaning patients taking 5 mg ertugliflozin actually lost more weight on average compared to patients taking the higher-dose, 15 mg ertugliflozin. This data supports the efficacy of Merck/Pfizer’s SGLT-2 inhibitor candidate, which was accepted for review by the FDA earlier this year – a regulatory decision is expected by January 2018, and we look forward to a four-product SGLT-2 inhibitor market (ertugliflozin would join J&J’s canagliflozin, Lilly/BI’s empagliflozin, and AZ’s dapagliflozin).

Dapagliflozin is Associated with Lower Risk of Hospitalization for Kidney Disease, Heart Failure, and All-Cause Death Compared to DPP-4i: CVD-REAL Nordic (165-LB)

A Norhammar, JW Eriksson, J Bodegard, M Thuresson, P Fenici, D Nathanson, M Kosiborod, HL Gulseth, T Nyström, and KI Birkeland

A subgroup analysis of CVD-REAL compared real-world renal and cardiovascular outcomes between type 2 diabetes patients starting treatment with SGLT-2 inhibitor dapagliflozin (AZ’s Farxiga) vs. DPP-4 inhibitors. Mean follow-up time was 0.94 years in the dapagliflozin arm vs. 0.99 years in the DPP-4 arm. Dapagliflozin (n=8,582) reduced risk for hospitalization for kidney disease by 62% (HR=0.38, 95% CI: 0.29-0.51, p<0.00) compared to DPP-4 inhibitors (n=25,746). The SGLT-2 agent was also associated with a 37% risk reduction for heart failure hospitalization (HR=0.63, 95% CI: 0.50-0.81, p<0.001) and with a 27% risk reduction for all-cause death (HR=0.73, 95% CI: 0.59-0.91, p=0.004) compared to DPP-4 inhibitors. CVD-REAL is an AZ-sponsored observational analysis of SGLT-2 inhibitors vs. other glucose-lowering drugs, and the “real-world” nature of the trial means that events were not adjudicated as they are in randomized controlled trials, and the findings are subject to possible confounding. That said, even if these values for relative risk reduction are somewhat inflated, the renal and cardioprotective benefits to SGLT-2 inhibitor therapy are quite remarkable. It’s great to see real-world evidence to back-up findings from major randomized controlled outcomes trials, including EMPA-REG OUTCOME for Lilly/BI’s Jardiance (empagliflozin) and CANVAS for J&J’s Invokana (canagliflozin). This is also the first post-hoc analysis of CVD-REAL (the initial results were presented at ACC 2017 in March) that compares SGLT-2 inhibitors vs. another specific therapy class – we’re eager to see more of these comparative analyses, especially SGLT-2 inhibitors vs. GLP-1 agonists since certain agents in both of these classes have positive CVOT data. We salute AZ and all the researchers for making this happen.

Combination Therapy of Canagliflozin and Teneligliptin in Japanese Patients with T2DM: Results from Phase 3 Studies (1194-P)

K Kaku, T Kadowaki, N Inagaki, K Kondo, K Nishimura, G Kaneko, N Maruyama, N Nakanishi, H Iijima, Y Watanabe, and M Goda

This poster displayed an integrated analysis of three phase 3 studies comparing canagliflozin/teneligliptin co-administration vs. monotherapy with either the SGLT-2 inhibitor (canagliflozin) or the DPP-4 inhibitor (teneligliptin). Two 24-week trials randomized Japanese participants with type 2 diabetes to canagliflozin vs. placebo as an add-on to a background of teneligliptin (n=138), or to teneligliptin vs. placebo as an add-on to a background of canagliflozin (n=154). Both studies showed superior A1c-lowering with the SGLT-2/DPP-4 combination vs. either agent alone: In the former, the A1c treatment difference was 0.88% in favor of canagliflozin (p<0.001 vs. placebo), dropping from a baseline A1c ~8%. In the latter, the A1c treatment difference was 0.94% in favor of teneligliptin (p<0.001 vs. placebo), also from a baseline A1c ~8%. A third, 52-week open label trial added canagliflozin onto a baseline regimen of teneligliptin (n=153). Sustained A1c improvements on combination therapy were observed throughout the one-year trial duration, and 82% of participants achieved clinically-meaningful A1c reductions and body weight reductions. This highlights one of the key benefits to SGLT-2/DPP-4 combos, in that they show superior glucose-lowering efficacy and weight loss efficacy, all the while offering a milder side-effect profile vs. either drug alone. Indeed, adverse events were well balanced across all groups, with the exception of genital mycotic infections which are expected to be higher with SGLT-2 inhibitor treatment (occurring in 1% of male trial participants and 11% of female trial participants in the third, 52-week study). These integrated results were the basis for a New Drug Application jointly-submitted by Mitsubishi Tanabe Pharma (which markets canagliflozin in Japan as Canaglu) and Daiichi Sankyo (which markets teneligliptin as Tenelia) to Japanese regulatory authorities earlier this year. A decision on this fixed-dose combination candidate, MT-2412, is expected in 2Q18.

Safety and Efficacy of Ertugliflozin in Combination with Sitagliptin in Subjects with T2DM Inadequately Controlled on Diet and Exercise: The VERTIS SITA Trial (1197-P)

B Lauring, S Miller, T Krumins, H Zhou, S Huyck, J Johnson, G Golm, S Terra, J Mancuso, and S Engel

This poster displayed 26-week results from Merck/Pfizer’s VERTIS SITA trial comparing combination therapy with SGLT-2 ertugliflozin/DPP-4 inhibitor sitagliptin (Merck’s Januvia) vs. placebo. The study randomized participants (n=291 patients with type 2 diabetes) to one of three arms: (i) 5 mg ertugliflozin/100 mg sitagliptin once-daily, (ii) 15 mg ertugliflozin/100 mg sitagliptin once-daily, or (iii) placebo. Patients in the lower dose combo group experienced a mean A1c reduction of 1.6% from a baseline 8.9% vs. a mean A1c reduction of 0.44% from a baseline of 9% for patients on placebo (p<0.001). Similarly, patients in the higher dose combo group experienced superior A1c reductions of 1.68% from a baseline 9% (p<0.001 vs. placebo). Defining A1c goal as <7%, 36% of 5 mg ertugliflozin participants and 31% of 15 mg ertugliflozin participants (both on top of sitagliptin) achieved this target by week 26 vs. only 8% of placebo participants (p<0.001 for both comparisons). The dual therapy was also associated with significant reductions in weight and systolic blood pressure. On average, body weight dropped 2.9 kg (6.4 lbs) for people on 5 mg ertugliflozin/100 mg sitagliptin vs. 0.9 kg (2 lbs) for people on placebo (p<0.001). Patients on 15 mg ertugliflozin/100 mg sitagliptin lost a mean 3 kg (6.6 lbs) over 26 weeks (p<0.001 vs. placebo). Baseline body weight was 91 kg (201 lbs) in the two dual therapy arms and was 95 kg (209 lbs) in the placebo arm. Systolic blood pressure declined by 2 mmHg in the lower dose combo group and by 4 mmHg in the higher dose combo group, but actually increased by a mean 2.4 mmHg among patients on placebo (p=0.011 and p<0.001, respectively). This trial saw little difference in adverse events across groups (and a generally low incidence of safety issues overall) as well as great retention – 291 were randomized, 282 completed all 26 weeks, and 254 completed on study medication. Fewer participants (~2% of both ertugliflozin/sitagliptin groups) discontinued treatment due to an adverse event vs. placebo (~3%). Ultimately, in patients with type 2 diabetes not at goal, co-initiation of ertugliflozin and sitagliptin could provide better glycemic control, weight loss, and lower blood pressure.

• These poster results were part of a range of VERTIS program studies presented at this ADA (also VERTIS MONO, VERTIS SITA2, and VERTIS FACTORIAL). Across the board, these posters and oral presentations emphasized the value of a fixed-dose SGLT-2/DPP-4 combination due to superior glucose-lowering, weight loss, and blood pressure-lowering efficacy. If approved by the FDA (and decisions on standalone ertugliflozin as well as this fixed-dose combination and a fixed-dose combination of ertugliflozin/metformin are expected by January 2018), this new oral combination will join a class with AZ’s Qtern (dapagliflozin/saxagliptin) and Lilly/BI’s Glyxambi (empagliflozin/linagliptin). We’re eager to see this approval, as we see the Merck/Pfizer duo as particularly fit to make a fixed-dose SGLT-2/DPP-4 combination a commercial success and to ensure wide patient access.

Long-Term Efficacy and Safety of Ertugliflozin Monotherapy in Patients with Inadequately Controlled T2DM Despite Diet and Exercise: The 52-Week VERTIS MONO Study (1208-P)

R Aronson, A Goldman, J Frias, A Darekar, B Lauring, S Huyck, and S Terra

Merck/Pfizer’s VERTIS MONO study of ertugliflozin (which was accepted for review by the FDA earlier this year) showed the SGLT-2 inhibitor’s A1c-lowering, weight loss, and blood pressure-reducing efficacy vs. placebo. Patients with type 2 diabetes and baseline A1c ~8% (n=461) were randomized to 5 mg ertugliflozin, 15 mg ertugliflozin, or placebo for 26 weeks, and then entered a “phase b” of the trial in which participants allocated to placebo and who also did not receive rescue therapy also received metformin for 26 weeks in phase B. Ertugliflozin was associated with dose-dependent, superior A1c reductions vs. placebo at week 26 (with a greater decline in the 15 mg arm vs. the 5 mg arm), but the mean A1c across all groups (including placebo) evened out once metformin was added to medication regimen. At week 52, the mean A1c drop was 1% for the placebo/metformin group, 0.9% for the low-dose ertugliflozin group, and 1% for the high-dose ertugliflozin group; 27.5% of participants in the placebo/metformin group achieved A1c goal <7% vs. 25.6% of those in the low-dose SGLT-2 group and 28.5% of those in the high-dose SGLT-2 group. Change in fasting plasma glucose was also similar across all study arms after one year: -29.3 mg/dl, -29 mg/dl, and -32.7 mg/dl for the placebo/metformin, 5 mg, and 15 mg cohorts, respectively (all from a baseline fasting glucose ~180 mg/dl). Both ertugliflozin groups experienced clinically-meaningful reductions in body weight and systolic blood pressure, though comparable results on body weight were also seen in the placebogroup after metformin was added. As expected for an SGLT-2 inhibitor, ertugliflozin was associated with an increased frequency of female genital mycotic infections, affecting 27% and 29% of the low- and high-dose groups, respectively (vs. 10% of the placebo/metformin group). All in all, the poster concludes that ertugliflozin offers good glycemic control and weight loss benefits to patients with type 2 diabetes inadequately controlled on diet/exercise alone, even though it’s unclear how the benefits distinguish the agent from metformin – we imagine there is more to the story here, although we also recognize cost as a key consideration and must note that metformin is generic and relatively inexpensive compared to the pricing we’d expect for a newly-approved SGLT-2 inhibitor.

Effect of Empagliflozin on Cardiac and Vascular Hemodynamic Markers by Subgroups of Age, SEx, and Hypertension in Patients with T2DM and High CV Risk: EMPA-REG OUTCOME (1452-P)

R Chilton, L Gullestad, D Fitchett, S Inzucchi, M Mattheus, H Woerle, and O Johansen

This new sub-analysis of the EMPA-REG OUTCOME trial explored the effect of longer-term (164 weeks) empagliflozin therapy on hemodynamics, arterial stiffness, and myocardial work burden. The EMPA-REG OUTCOME trial’s primary analysis had previously shown empagliflozin treatment to reduce the risk of cardiovascular death by 38%. The trial enrolled 7020 patients with type 2 diabetes and known CV disease who were randomized to either placebo, or 10 or 25 mg of empagliflozin. Median treatment duration and observation time were 2.6 and 3.1 years, respectively. Empagliflozin treatment resulted in significantly greater reductions in pulse pressure, mean arterial pressure, and double product (a measure of cardiac workload and an indirect measure of myocardial oxygen demand) at week 164 as compared to placebo. Reductions in these measures with either empagliflozin dose versus placebo held across age, gender, and systolic blood pressure groups.

Symposium: SGLT2 Inhibitors—Still More to Explore

Clinical Impact of SGLT2 Inhibitors on Bone—The FDA Perspective

Hyon J. Kwon, PhD (FDA, Silver Spring, MD)

With the safety of SGLT-2 inhibitors currently under a microscope, FDA’s Dr. Hyon Kwon provided insight on the fracture risk associated with J&J’s Invokana (canagliflozin) and AZ’s Farxiga (dapagliflozin) but not Lilly/BI’s Jardiance (empagliflozin). He positioned the label warnings for Invokana and Farxiga not as deterrents, but as a means to encourage thoughtful patient selection to mitigate fracture risk in the real world – we were happy to hear this perspective from FDA, since we’d hate for safety concerns to define the SGLT-2 inhibitor story when there are also tremendous glycemic, weight loss, and CV benefits to consider. Dr. Kwon noted that canagliflozin was only associated with a significantly increased risk for fractures in the CANVAS trial, but not in other studies within the Invokana clinical program, so heightened fracture risk may only apply to patients at high CV risk. An interim analysis of CANVAS found a hazard ratio of 1.51 in favor of placebo (95% CI=1.04-2.19), which doesn’t cross the line of unity and thus meets the threshold for statistical significance. Non-CANVAS studies reported a hazard ratio of 1.09 in favor of placebo (95% CI=0.71-1.66), but this fracture risk did not meet statistical significance. Dr. Kwon displayed graphs for time to first fracture in CANVAS, in which the curves diverge early on. He explained that a separation of curves <12 weeks after randomization suggests that fractures are due to falls rather than an impact on bone metabolism, an effect that would only accrue with longer duration of treatment. Moreover, interim CANVAS results showed a 60% increased risk of falls for participants on 300 mg canagliflozin vs. placebo (HR=1.60; 95% CI=1.11-2.32), which contributes to this hypothesis. It’s unclear if this increase in falls is a chance finding or if something about the canagliflozin causes increased risk of falls (through balance issues or confusion, perhaps?). As such, based on current data, the FDA cannot rule out that this particular SGLT-2 inhibitor may confer excess fracture risk for all patients, regardless of their CV risk factors. A pooled analysis of CANVAS and other Invokana clinical trials resulted in a hazard ratio of 1.32 in favor of placebo (95% CI=1.00-1.74). That said, we’re reserving judgement until we see the full, integrated results from CANVAs and CANVAS-R, which will be presented on Monday. In addition to long-awaited CV data, our ears will be perked for any safety details on the bone fracture risk (and the newly characterized amputation risk). Turning to Farxiga, Dr. Kwon showed that there was no imbalance in fractures between dapagliflozin-treated patients and placebo-treated patients overall, but that one study enrolling individuals with moderate renal impairment did find excess fracture risk associated with AZ’s SGLT-2 inhibitor. Fractures were most common in participants with eGFR between 11-45 ml/min/1.73m². This was added to the drug label under the “warnings & precautions” section, but again, this risk could be well-managed through diligent patient education, allowing many people with diabetes to still benefit from a highly-effective, advanced therapy.

• We think we speak for many at this meeting when we say we’re anxious for CANVAS to report full results on Monday afternoon. No matter what, this data will be telling – we have our fingers crossed for a statistically significant CV benefit that builds evidence for a cardioprotective class effect (following EMPA-REG OUTCOME) and highlights the therapeutic advantages of SGLT-2 inhibitors, but we’ll also need to scrutinize fracture data from the completed trial as well as data on amputations considering the FDA’s decision to add safety warnings for lower limb amputations to the Invokana label. All in all, our sense is that SGLT-2 inhibitors have a complicated risk-benefit profile and we’re always eager for more data to aid patients and providers in clinical decision-making regarding this class.

Clinical Role of SGLT2 Inhibitors – Current and Future

Julio Rosenstock, MD (Dallas Diabetes and Endocrine Center, Dallas, TX)

In a very candid presentation, Dr. Julio Rosenstock provided an overview of the many indications he envisions in the future of the SGLT-2 inhibitor class. While acknowledging that there has been a steady stream of safety warnings for the class, he emphasized that most of the concerns are manageable and the overall risk-benefit profile for these agents favor their use in a number of indications. Within type 2 diabetes, based on the EMPA-REG OUTCOME data and the CVD-REAL data, Dr. Rosenstock asserted that, it would be highly questionable for a patient with type 2 diabetes and a prior history of cardiovascular disease to not be on an SGLT-2 inhibitor, unless there was a contraindication, intolerance issues, or other clinical concern – he also appeared optimistic that the impressive cardiovascular benefit observed in EMPA-REG OUTCOME is a class effect, based on CVD-REAL. We certainly look forward to the CANVAS results presentation this Monday to potentially substantiate this! Further, Dr. Rosenstock suggested that SGLT-2 inhibitor and metformin combination therapy will increasingly become the preferred first line treatment for all patients with newly-diagnosed type 2 diabetes, not just those with established CV disease. He also suggested that SGLT-2 inhibitor/DPP-4 inhibitor fixed-dose combinations (FDC) will become the preferred second-line treatment for patients who are not well managed on metformin monotherapy – he argued that it makes little sense to intensify with only an SGLT-2 inhibitor or only a DPP-4 inhibitor when the combination of the two has been demonstrated to be more efficacious than either component. Beyond type 2 diabetes, Dr. Rosenstock forecasted a role for SGLT-2 inhibition in type 1 diabetes adjunct therapy. He acknowledged that there are clear safety issues – characterizing the highly publicized DKA risk as “real” – but emphasized that the risk is predictable, detectable and preventable. That said, Dr. Rosenstock shared rumors that Janssen is unlikely to pursue a type 1 diabetes indication for Invokana (canagliflozin) further, following phase 2 results. On the other hand, he was more optimistic about Janssen pursuing an obesity indication for a combination of canagliflozin/phentermine, which reported promising phase 2 data at ADA 2016. Dr. Rosenstock was also excited about the potential of SGLT-2 inhibitors in chronic kidney disease and in heart failure – several trials are ongoing for both of these indications and we’re similarly excited to see these results. Finally, Dr. Rosenstock also highlighted a potential role of SGLT-2 inhibitors in prediabetes and primary CV prevention. Indeed, J&J has previously shared plans to conduct a CVOT for Invokana in people with prediabetes and we’re very intrigued by this prospect as well.

SGLT-2 Inhibitors, Diabetic Ketoacidosis, and the Kidney

Matthew Weir, MD (University of Maryland, Baltimore, MD)

Dr. Matthew Weir reviewed the pathophysiology of SGLT-2 inhibitors, describing potential mechanisms for diabetic ketoacidosis (DKA) and for the CV and renal benefits associated with multiple members of the class, ultimately concluding that the “risk is very small and the upside is very substantial” for this therapy class as a whole. He compared the biochemical pathways of starvation to DKA and pointed to glomerular hyperfiltration, pro-inflammatory processes, and increased ATP production as possible mechanisms for SGLT-2 inhibitors’ renal and CV benefits. Dr. Weir discussed some of the more recent data on eGFR reductions with SGLT-2 agents (specifically looking at the findings in EMPA-REG OUTCOME), and shared that these reductions are likely not of significant concern. Looking forward, he called attention to additional considerations about newer therapies, including (i) their ability to be complementary with RAAS blockers, (ii) if effects remain at various blood pressures, and (iii) whether effects persist after treatment cessation. In conclusion, Dr. Weir strongly endorsed the use of SGLT-2 inhibitors, emphasizing the improvements in glycemic control, blood pressure reductions, and opportunities for CV and renal risk reduction, all of which outweigh the manageable DKA risk in his view (and ours).

Corporate Symposium: DCRI Evidence to Practice Series – Management of Diabetes for Heart Failure Patients (Sponsored by BI)

Latest Research Findings and Knowledge Gaps

Jennifer Green, MD (Duke University, Durham, NC)

In her introduction to this bright and early corporate symposium, Dr. Jennifer Green highlighted the substantial overlap between diabetes and heart failure (28%-44% of patients with heart failure also have diabetes) and reviewed the current evidence on the effects of specific diabetes drugs on heart failure. She explained that while the FDA-mandated cardiovascular outcomes trials of diabetes drugs have provided valuable information about heart failure outcomes, significant knowledge gaps remain. Specifically, she noted that i) CVOTs for diabetes drugs were not designed specifically to enroll patients with heart failure or evaluate heart failure outcomes; ii) the percentage of participants with heart failure varied in the different trials; iii) minimal details about heart failure outcomes were collected; iv) heart failure hospitalization was typically the only heart failure endpoint measured, leaving out a number of other relevant outcomes; and v) the physiological basis of the drugs’ positive or negative effects on heart failure has not been fully explained. Looking forward, Dr. Green argued that at a minimum, investigators should collect more detailed information on heart failure outcomes in future trials of diabetes drugs. We’ve heard a great deal about assessing BNP (a marker for heart failure) at baseline in diabetes CVOTs – of course, hindsight is 20/20 and we don’t expect this is possible in CVOTs that have already initiated, but we expect more rigorous assessments of heart failure at baseline will become the norm as heart failure is seen as an increasingly important endpoint in these trials. She also expressed interest in investigating diabetes drugs specifically in patients with heart failure (as Lilly/BI are currently doing in the EMPEROR trials of Jardiance [empagliflozin] and AZ is doing in the Dapa-HF trial of Farxiga [dapagliflozin]), conducting trials to determine the best drug for these patients, and assessing the effects of older diabetes drugs on heart failure risk. 

Case Presentations

Robert Mentz, MD (Duke University, Durham, NC), Darren McGuire, MD (UT Southwestern, Dallas, TX), Eldrin Lewis, MD (Brigham and Women’s Hospital, Boston, MA)

The majority of the corporate symposium centered around three case presentations involving patients with both type 2 diabetes and heart failure. The speakers agreed that metformin is currently the treatment of choice for this patient population. Dr. Darren McGuire noted that many physicians still shy away from using metformin in patients with heart failure because it was previously contraindicated, but many cardiologists are now specifically endorsing the drug for this population. The speakers were cautiously optimistic about the positive effects of Lilly/BI’s Jardiance (empagliflozin) on heart failure demonstrated in EMPA-REG-OUTCOME.  All three speakers expressed excitement about the results demonstrating a 38% risk reduction for cardiovascular death and 35% risk reduction for heart failure hospitalization with Jardiance vs. placebo in patients with type 2 diabetes and high cardiovascular risk. However, the consensus seemed to be that only results from the EMPEROR trials, which are specifically designed to investigate the impact of Jardiance on heart failure, will be able to establish the drug as a standard treatment for this population. This was interesting to hear – of course, we do not expect the FDA will include any indication for heart failure on the Jardiance label until results from these trials are available (given the fairly dismissive discussion of the heart failure secondary endpoint finding at last year’s Advisory Committee meeting on the EMPA-REG OUTCOME results). On the other hand, the ESC heart failure guidelines have already been updated to recommend empagliflozin as a potential treatment for those with type 2 diabetes and comorbid heart failure.

Questions and Answers

Dr. Darren McGuire (UT Southwestern, Dallas, TX): I’m convinced there’s heterogeneity among DPP-4 inhibitors. I would avoid saxagliptin and alogliptin because sitagliptin has a completely clean heart failure label. If a DPP-4 is used, I would use sitagliptin, but I’m not sure I would use one in this patient [in the hospital after an acute MI with diabetes and heart failure]. I think metformin is great. The EMPA-REG results were impressive but we didn’t have acute MI patients in that trial so I don’t really know what I’m doing. My gut instinct is that it’s logical and probably indicated to do empagliflozin. There’s a relatively preserved ejection fraction and little concern about GLP-1 agonists, so I’d probably prefer that over DPP-4 inhibitors. I’m comfortable with an A1c target of 7-8%.

Dr. Jennifer Green (Duke University, Durham, NC): If you switched from saxagliptin to sitagliptin, you would probably get the same glycemic control. If you stopped the DPP-4 inhibitor, you could increase the empagliflozin dose but would probably have an A1c increase. In the EMPA-REG trial, there were essentially comparable benefits with both doses, so I wouldn’t feel compelled to up-titrate the dose. There are lots of nuances.

Q: If you used sitagliptin, how would you handle the dose because of the patient’s impaired renal function?

Dr. McGuire: I would use a lower dose. But I would lean away from DPP-4 inhibitors because of the impaired renal function.

Q: How reliable is her eGFR?

Dr. McGuire: She’s having an acute MI and heart failure, so there’s likely acute kidney injury. We have to use the best evidence we have but we don’t know what her real kidney function is.

Q: Should we be focusing on obesity management?

Dr. McGuire: Absolutely. We need your help. People think about cardiac rehab as a treadmill and exercise, but it’s a structured comprehensive program. We should use cardiac rehab resources for eligible people. Obesity should be a focus of the intervention as well.

Dr. Eldrin Lewis (Brigham and Women’s Hospital, Boston, MA): You hear about the obesity paradox in heart failure. I don’t think it’s a paradox. If you’re obese, you may be short of breath for other reasons, so you may be healthier than someone of normal weight who has the same degree of dyspnea. We should be emphasizing weight loss for control of diabetes and heart failure symptoms.

Dr. Green: There’s some data on the association between glucose-lowering therapies and their effect on weight and heart failure outcomes. The suggestion is that therapies associated with weight loss are associated with reduced heart failure risk and those associated with weight gain are associated with higher risk. It’s an area ripe for further exploration.

Corporate Symposium: CVOTs and Combination Therapy: Updates and Advances at ADA 2017 (Sponsored by AstraZeneca)

Cardiovascular Outcomes Trials (CVOTs): Clinical Application of Current Data and a Sneak Peek into the Future

Carol Wysham, MD (University of Washington, Spokane, WA); Hertzel Gerstein, MD (McMaster University, Ontario, Canada)

Drs. Carol Wysham and Hertzel Gerstein reviewed all the major CVOT data on diabetes drugs that has been published so far, and shared pearls of wisdom about how to translate these findings into real-world clinical practice. Dr. Gerstein positioned GLP-1 agonists as the frontrunners in terms of demonstrating CV benefit, with both the LEADER trial for Novo Nordisk’s Victoza (liraglutide) and the SUSTAIN 6 study for Novo Nordisk’s semaglutide showing meaningful CV risk reduction. That said, SGLT-2 inhibitors like Lilly/BI’s Jardiance (empagliflozin) and J&J’s Invokana (canagliflozin) have also demonstrated superiority vs. placebo in reducing risk for three-point MACE (non-fatal MI, non-fatal stroke, or CV death), and these agents come with the convenience of oral dosing (whereas GLP-1 agonists are injectable therapies). Dr. Wysham emphasized that CVD-REAL showed SGLT-2 inhibitors to be associated with a very dramatic risk reduction for heart failure hospitalization and all-cause death. A majority of European participants in CVD-REAL (92%) were taking AZ’s SGLT-2 inhibitor Farxiga (dapagliflozin), while a majority of US participants were taking Invokana (76%) – Dr. Wysham underscored this point to clarify that she wouldn’t necessarily recommend switching patients off dapagliflozin onto empagliflozin right now. AZ’s own CVOT for dapagliflozin, DECLARE, is scheduled to complete in April 2019.

Oral Combination Therapy for T2D: What, Why, and How Explored

Julio Rosenstock, MD (University of Texas, Dallas, TX); Melanie Davies, MD (University of Leicester, UK)

Drs. Julio Rosenstock and Melanie Davies led this interactive discussion on oral combination therapies for type 2 diabetes, covering DPP-4/metformin tablets, SGLT-2/metformin tablets, and SGLT-2/DPP-4 tablets including AZ’s Qtern (dapagliflozin/saxagliptin). The duo positioned combination therapy as a solution to therapeutic inertia. The status quo in diabetes management is still the treat-to-fail paradigm, with healthcare providers trying medications in a stepwise fashion. Instead, Drs. Rosenstock and Davies advocated for early intervention with simultaneous medications, or better yet, with a fixed-dose combination therapy. They presented Qtern (and other SGLT-2/DPP-4 combo products like Lilly/BI’s Glyxambi) as a rational choice in diabetes care: These agents come in convenient oral doses, they lower risk of hypoglycemia and promote weight loss, they show superior glucose-lowering efficacy vs. either drug alone, and they eliminate some patient barriers by turning two co-pays into one. Diabetes treatment guidelines are starting to recommend combination therapy earlier on, especially for patients with high baseline A1c, but Drs. Rosenstock and Davies suggested that this change needs to happen faster. We’re certainly intrigued by the promise of fixed-dose SGLT-2/DPP-4 combinations, and we’re glad to note AZ’s commitment to Qtern given its strong clinical profile. Moreover, we love the argument that combination therapy could circumvent therapeutic inertia, which continues to be a problem leading to suboptimal diabetes care.

Insulin Therapy

Symposium: Cardiovascular Safety of Insulin Degludec vs. Insulin Glargine in Patients with Type 2 Diabetes at High Risk of Cardiovascular Events (DEVOTE) Trial Results

Introduction and Trial Design

Steven Marso, MD (University of Missouri, Kansas City, MO)

Dr. Steven Marso set the stage by presenting the trial design for DEVOTE. This randomized, double-blind, treat-to-target trial (n=7,637) enrolled people with type 2 diabetes on at least one diabetes therapy and an A1c >7% or <7% with basal insulin treatment at least 20 units/day. The study population had a high-risk cardiovascular profile; enrollment criteria included cardiovascular or chronic kidney disease for people over the age of 50 and the presence of cardiovascular risk factors for people over the age of 60. This global population included participants from five continents, 20 countries, and 438 trial sites. As is typical for CVOTs, the primary endpoint was time from randomization to first occurrence of a three-point MACE (non-fatal MI, non-fatal stroke, or CV death). Secondary endpoints included rate and incidence of severe hypoglycemia episodes.

Cardiovascular Outcomes

Darren McGuire, MD (University of Texas Southwestern Medical Center, Dallas, TX)

Dr. Darren McGuire took the stage to discuss the primary cardiovascular outcomes from DEVOTE. Novo Nordisk’s next-generation basal insulin Tresiba (insulin degludec) met its primary endpoint by demonstrating non-inferiority compared to standard of care insulin glargine (Sanofi’s Lantus) for three-point MACE (non-fatal MI, non-fatal stroke, and CV death). The hazard ratio (HR) point estimate was in the “right direction” at 0.91, but did not achieve statistical significant for superiority (95% CI:0.78-1.06, p<0.001 for non-inferiority, p=0.21 for superiority). Expanded MACE (including hospitalization for unstable angina) was non-inferior as well (HR=0.91, 95% CI:0.80-1.05, p=0.22), and Tresiba additionally demonstrated non-inferiority for each component of the MACE endpoint, with point estimates to the “left of unity” (meaning <1.0) in each case, including non-fatal MI (HR=0.85, 95% CI: 0.68-1.06, p=0.15), non-fatal stroke (HR=0.90, 95% CI: 0.65-1.23, p=0.50), and hospitalization for unstable angina (HR=0.95, 95% CI:0.68-1.31, p=0.74). Similarly, point estimates for all reported mortality endpoints were in the “right direction,” though not statistically significant for superiority, including CV death (HR=0.96, 95% CI: 0.0.76-1.21), all-cause mortality (HR=0.91, 95%CI:0.76-1.11), CV death excluding undetermined cause of death (HR=0.91, 95% CI: 0.69-1.20), and non-CV death (HR=0.84, 95% CI: 0.60- 1.16). 

Source: NEJM

• All in all, we can certainly rest assured that Tresiba is at the very least safe from a CV standpoint (though we cannot draw any definitive conclusions about potential benefit). That said, non-inferiority in and of itself is reassuring given Tresiba’s long and complicated regulatory history. As a reminder, the product’s first regulatory submission in the US received a Complete Response Letter (CRL) from the FDA, requesting a CVOT to further investigate a signal for increase expanded MACE risk observed in the phase 3 trials. The FDA’s eventual approval based on firewalled interim data was certainly reassuring on this front and we’re pleased to get our hands on full CVOT data that suggests not even a whiff of increased risk for Tresiba.
• The robustness of these results are underscored by the fact that the DEVOTE study population was selected to reflect the global population of people with type 2 diabetes. Between the Tresiba (n=3,818) and insulin glargine (n=3,819) arms, participants aged 65 years, an average diabetes duration of 16 years, a BMI of 33.6 kg/m3, and an A1c of 8.4%. Respectively, 86% and 85% of participants had established cardiovascular disease or chronic kidney disease and the remaining 14% and 15% had cardiovascular risk factors.

Glycemic Efficacy and Hypoglycemia

Bernard Zinman, MD (University of Toronto, Canada)

The great Dr. Bernard Zinman presented the very impressive hypoglycemia and glycemic efficacy findings from the DEVOTE trial. In many ways, while these were all secondary endpoints, these findings were the real headliners of the study – indeed, the independent commentary from hypoglycemia expert Dr. Elizabeth Seaquist focused almost entirely on the hypoglycemia results. The results are a big win to be sure: Tresiba was associated with a very significant 40% relative risk reduction in the overall rate of severe hypoglycemia compared to Lantus (HR=0.60, 95% CI 0.48-0.76, p<0.001 for superiority) and a whopping 53% reduced risk for nocturnal severe hypoglycemia (HR=0.47, 95% CI: 0.31-0.73, p<0.001). (Amazing confidence intervals.) Severe hypoglycemia was adjudicated in the study and defined as low blood glucose requiring the assistance of another person – in total, 1,005 events were sent for adjudication and the independent confirmed 752 events as severe hypoglycemia for the analysis. 4.9% of participants in the Tresiba group experienced one or more episodes of severe hypoglycemia, compared to 6.6% of participants in the Lantus group (odds ratio: 0.73; 95% CI: 0.60-0.89; p<0.001 for superiority). Overall, a participant taking Tresiba was 27% less likely to experience one or more episodes of severe hypoglycemia (HR=0.73, 95% CI:0.60-0.89, p<0.001).

Source: NEJM

• Notably, these reductions in hypoglycemia occurred in the context of virtually identical low mean A1cs at the end of the trial and lower fasting plasma glucose. Mean A1c was 7.55% in the Tresiba group and 7.5% in the Lantus group (baseline A1c=8.4%).  The end-of-trial A1c difference between the two arms was estimated at 0.01% (p=0.78). On the other hand, mean fasting plasma glucose (FPG) was 7.2 mg/dl lower in the Tresiba group compared to the Lantus group at the end of the trial (128 mg/dl vs. 136 mg/dl, p<0.001). This was driven by a larger reduction in FPG in the Tresiba group – 40 mg/dl vs. 35 mg/dl. The end-of-trial average basal insulin dose was slightly but significantly higher in the Tresiba group (2 units higher than average in Lantus group, p=0.04).
• Based on a subgroup analysis, it appears that the severe hypoglycemia benefit of Tresiba is more pronounced in those with established CV disease than in those without. There is a very clear 48% rate reduction for severe hypoglycemia in those with established CV disease at baseline (HR=0.52, 95% CI: 0.40-0.66). On the other hand, the point estimate among those with risk factors for CV disease – but no established CV disease – actually trended slightly toward increased risk at 1.24, though the confidence intervals were very wide and crossed the line of unity (95% CI: 0.65-2.38). Very notably, the p-value for interaction was 0.014. We’ve seen some previous analyses (based on the very large TECOS dataset) suggesting that those with a history of a previous CV event are more likely to experience subsequent severe hypoglycemia – suggesting that those with established CV disease at baseline are more vulnerable to hypoglycemia. While of course this subgroup analysis is only exploratory and hypothesis-generating, we’re intrigued by the implication that Tresiba therapy could perhaps offer hypoglycemia benefit to those who are most vulnerable and most at risk. We’ve increasingly heard some suggest that older patients, more frail patients (many of whom have had a previously hypoglycemic event) should be treated to higher A1c targets due to concerns about hypoglycemia. At the same time, some of these same thought leaders advocate for the use of human insulins in patients who are unable to afford newer analogs (including older patients in the Medicare Part D “donut hole”) and argue that insulin analogs – including next-generation analogs like Tresiba – offer only “incremental benefits”. We hope that long-term, compelling data like these findings from DEVOTE can help improve reimbursement and access to these drugs and allow older patients achieve lower A1c targets safely. We also hope that providers and others in the community who are concerned about both hypoglycemia and cost do more to advocate for the inclusion of these next-generation agents on formularies, etc.
  
  • There was no heterogeneity in effect for differences in sex, age, BMI, renal function, diabetes duration, baseline insulin regimen, or region.

• The full results offered a very exciting and impressive – but limited – look into the impact of Tresiba on outcomes beyond A1c. The data released thus far does not mention impact on weight – we hope to see this and other outcomes beyond A1c in future analyses. “Mild-to-moderate” blood glucose-confirmed hypoglycemia was not adjudicated in this trial and it’s unclear if any data on this front was collected – we certainly hope so as “less-severe” levels of hypoglycemia still have enormous quality of life and productivity implications for patients. We continue to believe that CGM studies would be enormously helpful in characterizing the benefit of next-generation insulin products especially (but other drugs as well) and we wish that CGM data could have been gathered for this large and long-term study (though, of course, we recognize that this study initiated many years ago and CGM accuracy has only relatively recently tremendously improved – at least relatively speaking).

Safety

Richard Pratley, MD (Florida Hospital Diabetes Institute, Orlando, FL)

Dr. Richard Pratley reviewed safety outcomes from DEVOTE, which were largely similar between Tresiba- and Lantus-treated participants, indicating that insulin degludec is safe and well-tolerated. There were 1,473 serious adverse events in the Tresiba arm of the trial, affecting 39% of patients vs. 1,517 serious adverse events in the Lantus arm, affecting 40% of patients. Severe adverse events occurred in 25% of both the Tresiba and Lantus groups (945 and 962 events, respectively). Adverse events leading to treatment discontinuation occurred in 5% of the Tresiba group vs. 6% of the Lantus group (200 and 222 events, respectively) – 24 of these events were reported by investigators as probably/possibly related to insulin degludec, while 31 were probably/possibly related to insulin glargine. He called special attention to neoplasms, likely because of age-old concerns that insulin, as a growth factor, heightens cancer risk (though these worries have dissipated with additional studies, including ORIGIN). In DEVOTE, neoplasms were classified by one chairman and two independent oncologists, who sorted events into categories for malignant, benign, and unclassifiable. The hazard ratio for benign neoplasm was 1.37 in favor of Lantus, though this did not reach statistical significance (95% CI: 0.76-2.47). The hazard ratio for malignant neoplasm was 0.94 in favor of Tresiba, but there was no statistically significant signal for risk reduction (95% CI: 0.71-1.24). All in all, there were 45 benign neoplasms observed during the course of the trial (26 in the degludec group and 19 in the glargine group) and 192 malignant neoplasms (93 in the degludec group and 99 in the glargine group). These safety findings underscore Tresiba’s non-inferior profile vs. Lantus, which holds true not only for CV effects, but for all adverse events as well.

• Dr. Pratley listed 16 adverse events occurring at a frequency ≥1% in DEVOTE, but emphasized that they were all equally likely to happen whether a patient was randomized to insulin degludec or insulin glargine. Hypoglycemia reported as an SAE was more common with Tresiba then glargine (see table), but adjudicated events (actually numerically higher in number as they were captured on a special form) were lower. This likely an effect of the reporting structure.  The adjudicated events are the most accurate representation of the difference in hypoglycemia risk. Other adverse events included atrial fibrillation, acute MI, angina pectoris, angina unstable, coronary artery disease, MI, congestive cardiac failure, non-cardiac chest pain, cellulitis, pneumonia, fall, hypoglycemia, ischemic stroke, transient ischemic attack, acute kidney injury, and chronic obstructive pulmonary disease. Frequency on each of these is displayed in the table below.

Conclusion and Clinical Implications

John Buse, MD (University of North Carolina, Chapel Hill, NC)

Dr. John Buse delivered concluding remarks on the DEVOTE full results, putting this trial into context with BEGIN, SWITCH 1 and SWITCH  2, and our knowledge to-date of how hypoglycemia affects CV risk and patient quality of life. One of the most important takeaways, in his view and ours, is that the significant 40% risk reduction for severe hypoglycemia at a similar A1c level and the 53% risk reduction for severe hypoglycemia overnight corroborate Tresiba’s hypoglycemia benefit as reported in BEGIN, SWITCH 1, and SWITCH 2. Novo Nordisk has submitted SWITCH 1 and SWITCH 2 data to the FDA for inclusion on the Tresiba label (decision expected in July), and this label update was recently EMA-approved. Novo Nordisk has also submitted the DEVOTE data to both the FDA and the EMA. Busy patients/providers deserve ready access to information on empirically-grounded benefits, such as lower risk for hypoglycemia, particularly significant hypoglcyemia, a key outcome beyond A1c metric. Fear of hypoglycemia affects patients and providers alike, with 79% of type 1 patients and 58% of type 2 patients who experience a severe episode opting to decrease their insulin dose (leading to suboptimal glycemic control). Similarly, 72% of PCPs and 79% of diabetes care specialists endorse that they would treat patients more aggressively if hypoglycemia was not a concern. Dr. Buse also shared findings from a large, systematic metaanalysis that linked hypoglycemia to a significantly increased risk for all-cause mortality (HR=1.8, 95% CI: 1.5-2.2), CV mortality (HR=2.2, 95% CI: 2.0-2.4), and major CV events (HR=2.3, 95% CI: 1.1-5.0). While the decrease in hypoglycemia seen in DEVOTE wasn’t sufficient to significantly lower CV events and CV death for people on Tresiba vs. Lantus, Dr. Buse emphasized that reducing the severity and frequency of hypoglycemia could have an independent positive impact on a patient’s cardiovascular health. What’s more, helping patients avoid hypoglycemia allows for best practice diabetes management and substantially improves quality of life for people living with this chronic disease. Although cost wasn’t explicitly mentioned during Dr. Buse’s presentation, we know hypoglycemia incurs major avoidable costs on the healthcare system due to hospitalizations, emergency care, productivity loss, and more. We imagine the profound hypoglycemia benefit in DEVOTE could come into play for Tresiba in formulary negotiations – we’d surely love to see a health economic analysis predicting cost-savings. Dr. Buse announced that further analysis from DEVOTE, focused on the associations between glycemic control, glycemic variability, and outcomes, will be presented at EASD 2017 in Lisbon, Portugal. We can’t wait.

Independent Commentary

Elizabeth Seaquist, MD (University of Minnesota, Minneapolis, MN)

University of Minnesota and the International Hypoglycemia Study Group’s Dr. Elizabeth Seaquist provided a thoughtful and balanced independent commentary on the DEVOTE results. She praised the strengths of the trial design, including the randomized, double-blinded, event-driven, and treat-to-target design with well-defined endpoints. She highlighted the large size of the trial as well (n=7,637 at 434 sites on five continents), commenting that the study’s “generalizability to patients with type 2 diabetes is assured.” The very low dropout rate (2%), standardized titration protocol, rigorous adjudication of severe hypoglycemia, and systematic collection of adverse events also improved Dr. Seaquist’s confidence in the findings and conclusions. That said, Dr. Seaquist also pointed out several weaknesses in the data that was collected – one was directed more at the design of the trial while the other two were directed at the limited clinical information provided by the trial. On the first, Dr. Seaquist noted investigators in the trial could modify the titration protocol based on clinical judgement and it’s unclear if these modifications were applied in a standardized way between the two arms of the trial. In terms of the information included in the endpoints, Dr. Seaquist underscored that data on moderate symptomatic hypoglycemia and on hypoglycemic events with blood glucose levels ≤54 mg/dl were not collected. The former is the most common kind of hypoglycemia experienced by patients and the lack of inclusion of this endpoint makes it difficult to assess the impact of Tresiba on more common forms of hypoglycemia. The latter information would be important and useful to have since it’s known that impaired awareness of hypoglycemia is more likely to develop with recurrent episodes of hypoglycemia with blood glucose ≤54 mg/dl. Dr. Seaquist also highlighted additional questions that should be addressed using the DEVOTE data, including (i) Was the reduction in severe hypoglycemia in the Tresiba arm associated with a reduction in healthcare costs?; and (ii) Was the reduction in severe hypoglycemia in the Tresiba arm associated with improved quality of life/sleep and reduced fear of hypoglycemia (this is yet another question that would have been aided by greater collection of hypoglycemia data in our view)? Furthermore, she highlighted several questions that DEVOTE leaves unanswered: (i) Does Tresiba reduce hypoglycemia more relative to Lantus in patients with severe renal impairment?; (ii) What is the relative impact of Tresiba vs. Lantus on severe hypoglycemia in insulin-naïve patients?; and (iii) How do the effects of Tresiba on glycemic control and hypoglycemia in type 2 diabetes compare to Toujeo (U300 insulin glargine)?

Oral Presentations: Landscape of Therapeutic Trials in Type 2 Diabetes

Efficacy and Safety of Insulin Degludec/Liraglutide (IDegLira) vs. Basal-Bolus (BB) Therapy in Patients with Type 2 Diabetes (T2D): DUAL VII Trial

Liana Billings, MD (North Shore University Health System, Skokie, IL)

To numerous rounds of thunderous applause, Dr. Liana Billings (North Shore University Health System, Skokie, IL) presented the impressive results of the DUAL VII trial comparing the safety and efficacy of Novo Nordisk’s Xultophy (insulin degludec/liraglutide) versus traditional basal-bolus therapy in type 2 diabetes. People with type 2 diabetes on insulin glargine (n=506) were randomized in an open-label setting to once-daily Xultophy for 26 weeks or to basal-bolus regimen with insulin glargine and insulin aspart. The trial met its primary endpoint by demonstrating that treatment with Xultophy is non-inferior to basal-bolus therapy with respect to A1c lowering (-1.48% vs. -1.46%, baseline A1c 8.2%) and furthermore demonstrated superiority for a host of secondary outcomes. Compared to basal-bolus therapy, average total daily insulin dose among those taking Xultophy was less than half that of those on basal-bolus therapy (40 vs. 84 units; p<0.001). The end-of-trial body weight difference was also substantially in favor Xultophy (-0.93 kg [2.1 lbs] vs. +2.64 kg [5.8 lbs], p<0.001). Very notably, Xultophy additionally proved superior in terms of hypoglycemia: only 20% of participants in the Xultophy arm experienced blood glucose-confirmed symptomatic or severe hypoglycemia during the study period, versus a whopping 53% of participants in the basal-bolus therapy arm, an extremely impressive 89% risk reduction (HR= 0.11; 95% CI: 0.08-0.17; p<0.0001). Xultophy’s safety profile remained consistent with previous findings; unsurprisingly, nausea was the most frequently-reported adverse event (28 patients in the treatment arm vs. 4 in the basal-bolus arm), but Dr. Billings pointed out that only <3% of the participants in the IDegLira arm experienced nausea at any given time. Indeed, as we understand it, the basal insulin component of these combinations can mitigate the GI side effects typically associated with GLP-1 agonists. During Q&A, the esteemed Dr. Julio Rosenstock deemed this the "most robust, most impressive piece of data I've seen in years." We are equally impressed with these clinical advantages for Xultophy over traditional basal-bolus treatment regimen – especially in terms of the crucial outcome of hypoglycemia risk reduction – and hope these findings help to advance the uptake of the emerging class of GLP-1 agonist/basal insulin co-formulations. We expect to continue to see increasing preference for GLP-1 agonists over prandial insulin as a basal intensification option, and DUAL VII lends strong clinical evidence for this choice. We’ll be back with more on DUAL VII with our take on additional analyses, presented in two posters: one on the cost effectiveness of Xultophy (981-P) and another detailing patient-reported outcomes from DUAL VII (124-LB). While we are happy to see this research, it is our sense that it is extremely challenging for patients to actually gain access to this therapy, despite now years of robust praise.

Efficacy and Safety of Exenatide QW vs. Placebo Added to Insulin Glargine in Uncontrolled Basal-Insulin Treated Type 2 Diabetes: DURATION-7 Trial

Juan Frias, MD (National Research Institute, Los Angeles, CA)

In a packed oral session, Dr. Juan Frias (National Research Institute, Los Angeles, CA) presented the results from the DURATION-7 study, demonstrating clinical glycemic and weight benefits for AZ’s GLP-1 agonist Bydureon (exenatide once-weekly) as an add-on to insulin therapy in people with type 2 diabetes. Participants already on insulin therapy (n=461) were randomized to once-weekly Bydureon or placebo in combination with their existing insulin regimen. With Bydureon, participants experienced a significantly greater mean reduction in A1c (-1.0% vs. -0.3%, baseline A1c=8.5%, p<0.01) after 28 weeks, and 25% more patients in the Bydureon treatment arm achieved an A1c of <7% by the end of the study. Therapeutic intensification with Bydureon furthermore reduced fasting plasma glucose and 2-hour postprandial glucose by an average of 9 mg/dl (p=0.028) and 27 mg/dl (p<0.001) versus placebo, respectively. Notably, participants in the Bydureon arm additionally lost an average of 1.5 kg (3.3 lbs) relative to placebo (p<0.001), and 20% more participants using Bydureon achieved the composite endpoint of an A1c <7% with no weight gain or major hypoglycemia. Participants taking add-on Bydureon also experienced a 2 unit/day decrease in daily insulin requirements, but this did not achieve statistical significance (p=0.07). Adverse events were not significantly different between the treatment and placebo arms (125 vs. 133 events); gastrointestinal complaints were numerically higher in the exenatide group (35 vs. 25 events), as expected with a GLP-1 agonist, and no severe hypoglycemia events occurred in either treatment arm. Together these results underscore the superiority of exenatide once-weekly in combination with basal insulin over basal insulin therapy alone.

Oral Presentations: ADA Presidents Oral Session

Efficacy and Safety of Oral Basal Insulin: Eight-Week Feasibility Study in People with Type 2 Diabetes (T2DM)

Leona Plum-Mörschel, PhD (Profil, Mainz, Germany)

In the very last presentation of ADA 2017, Dr. Leona Plum-Mörschel (Profil, Neuss, Germany) shared phase 2a data for Novo Nordisk’s recently discontinued oral insulin candidate. The oral formulation paired longer-acting insulin analog insulin 338 with an absorption enhancer – Dr. Plum-Mörchel emphasized that oral delivery allows for insulin absorption via the portal vein, which could potentially translate into more physiologic action and less hypoglycemia. The eight-week trial randomized 50 insulin-naïve patients with type 2 diabetes to once daily oral insulin 338 or once daily insulin glargine injection (Sanofi’s Lantus). The trial was conducted in a double-blind, double-dummy manner – participants either took active oral insulin 338 and injectable placebo or injectable insulin glargine and oral placebo. All other diabetes medications except metformin and DPP-4 inhibitors were discontinued during the two-week washout period. At baseline, participants had a mean A1c of 8.1% in the oral insulin 338 arm and 8.2% in the insulin glargine arm. Insulin dose over the eight-week period rose comparably in both treatment groups and the end-of-trial treatment ratio was 347 nmol of oral insulin 338 to one unit of insulin glargine. Oral insulin 338 was found to be non-inferior to insulin glargine on a number of glycemic endpoints, including the primary endpoint of fasting plasma glucose (5.2 mg/dl higher with oral insulin, p=0.46), 10-point plasma glucose profile, A1c (0.3% higher with oral insulin, p=0.077), fructosamine (9.6 umol/l higher with oral insulin, p=0.37), and fasting C-peptide (0.02 nmol/l lower with oral insulin, =0.68). Notably, the only statistically significant finding was an increase in variability in fasting plasma glucose profiles over time with oral insulin 338 compared to insulin glargine (p=0.0060). That said, despite the increase in variability, fewer hypoglycemic events occurred in the oral insulin 338 arm (seven events in six patients) than in the insulin glargine arm (11 events in six patients) – fortunately, there were no reported episodes of severe hypoglycemia. The rate of other adverse events in the trial were similar across the two arms of the study, with no treatment-emergent serious adverse events, no severe adverse events, and no medical events of special interest. Further, Dr. Plum-Mörschel shared that there were no clinically significant findings in vital signs, ECG, physical examination (including fundoscopy), or safety laboratory data. Overall, the trial demonstrates the feasibility of glycemic management via oral insulin delivery, though it’s not clear that this candidate offers any substantial benefit over current insulin formulations, other than the convenience of oral dosing. That said, dose titration for oral insulin remains a complex prospect and, given the increasing popularity of non-insulin alternatives for type 2 diabetes (including GLP-1 agonists – which will soon be offered in oral and implantable formulations – and SGLT-2 inhibitors) that may delay the need for insulin initiation altogether. Given the increasingly high bar for new diabetes drugs, Novo Nordisk’s robust clinical development pipeline, and the company’s recent shift in its R&D priorities to focus on truly disruptive diabetes therapies and diabetes-adjacent indications, we’re not surprised by the decision not to pursue this candidate further given this data.

Oral Presentations: Hospital-Based Care and Diabetes – Adherence to Diabetic Care Strategies

How Much Does Adherence to Insulin Influence Glycemic Control?

Julie Lauffenburger, PhD (Harvard University, Boston, MA)

Dr. Julie Lauffenburger presented results from an analysis of insurance claims data designed to identify independent predictors of good glycemic control and quantify the extent of each factor’s predictive value. The analysis involved 690 patients with good glycemic control (A1c <8%) and 733 patients with poor control (A1c >8%). Investigators found that independent predictors of good control included age, mail order use, rapid-acting insulin use, insulin lispro use, insulin persistence, number of fills for insulin testing supplies, endocrinologist visits, and number of different pharmacies used. Of these factors, those considered potentially modifiable yielded a Net Reclassification Index (NRI) value of 0.38, meaning that modifying those variables could move 38% of the patients in the poor control group to the good control group or vice versa. Individual factors with the highest NRI were insulin therapy (0.28), lifestyle (21%), and provider and pharmacy (30%). A chi square analysis found that 76% of the variation in glycemic control was attributable to modifiable factors. Individual factors that explained most of the variation were provider and pharmacy (35%), insulin therapy (31%), lifestyle (12%), and insulin persistence (4%). Dr. Lauffenburger concluded that factors related to insulin therapy seem to be the most influential in predicting glycemic control, emphasizing that persistence is a fairly strong factor in itself. This underscores the need to empower patients to be more engaged in their medication regimen and other aspects to diabetes management, given that persistence itself could move so many individuals into the favorable category of good glycemic control (which, importantly, could translate to better health outcomes overall).

Questions and Answers

Q: I would think defining adherence to insulin would be more challenging than adherence to a once-daily pill. The number of units prescribed is not necessarily what the person takes or what the physician instructs them to take. What was your definition of insulin persistence?

A: The challenge with insulin in particular is that it’s about the days’ supply. When you calculate medication adherence or persistence, that’s what the pharmacist inputs. The persistence measure we used was published in Endocrine Practice. We looked at the first time they filled the prescription and the second time and divided patients into percentiles based on the time between the first and second fill. If the time between the first and second fill was longer than the 90th percentile, they were labeled non-adherent. If they didn’t fill it for 30-60 days after we thought they should, they were non-adherent.

Q: I’m fascinated by the results showing that payment for use of testing supplies was related. A lot of that is a function of the health insurer. Was there any variability that this insurer had in co-payments? Was it a large enough variability to examine?

A: The co-pays were fairly right-skewed. There was a decent degree of variation, largely associated with which insulin products patients were receiving.

Posters

A Novel Formulation of Insulin Lispro Containing Citrate and Treprostinil Shows Faster Absorption and Improved Postprandial Glucose Excursions vs. Humalog in Patients with T1DM (959P)

C Kazda, J Leohr, R Liu, S Reddy, MA Dellva, ST Lim, MT Loh, MP Knadler, T Hardy, L Plum-Moerschel

Lilly presented new data on its novel ultra-rapid insulin formulation LY900014, demonstrating that the candidate shows faster absorption and improved postprandial glucose excursions vs. Lilly’s Humalog (insulin lispro) in type 1 diabetes. Type 1 diabetes patients (n=30) were randomized to either LY900014 or Humalog. Results demonstrated that the LY900014 group had accelerated early insulin lispro absorption compared to the Humalog group: LY900014 reduced the time to early half-maximal drug concentration by 36.5% (p<0.0001) and the insulin lispro area under the concentration curve vs. time from 0 to 30 min post dose increased by 123% (p<0.0001) compared to Humalog. Additionally, the total glucose excursion over the 5-hour test-meal was significantly reduced by 44% for LY900014 vs. Humalog. We will have more information to follow on how long the insulin “lasts” etc. Regarding tolerability and adverse events, the type 1 patient population demonstrated no differences in local tolerability and the number or severity of hypoglycemic events. As a reminder, LY900014 is Lilly’s internally-developed candidate that could begin phase 3 trials by the end of 2017. This ultra-rapid insulin has recently received more attention after the disappointing termination of Lilly’s partnership with Adocia on the phase 3-ready ultra-rapid insulin BioChaperone Lispro (see its data from ADA 2016). For more on Lilly’s discussion around the new candidate, please see our 4Q16 update.

• LY900014’s formulation contains locally-acting excipients, citrate and trepostinil, to help accelerate insulin lispro absorption with the goal of providing ultra-rapid prandial insulin. Specifically, citrate increases vascular permeability at the injection site and treprostinil accelerates insulin lispro absorption by local vasodilation with no measurable systemic exposure. With this formulation, the goal is that LY900014 will more closely mimic physiologic prandial insulin secretion, improving postprandial glucose control and allowing greater flexibility in insulin administration timing.

Superior Glycemic Control with a Glucose-Responsive Insulin (GRI) (961P)

M Moore, D Kelley, M Smith, P Zafian, T Ye, S Lin, N Kaarsholm, R Nargund, M Van Heek, B Farmer, P Williams, A Cherrington

Findings from a preclinical study of Merck’s glucose-responsive insulin candidate (a lectin-bound insulin analog – it’s unclear if this is the same phase 1 MK-2640 GRI candidate) were presented in a poster. The study investigated the insulin in a dog model (n=8) vs. canine or human insulin, with each animal receiving both treatments in random order. Infusion of the insulin was adjusted in a low-glycemic condition to match canine/human insulin levels to bioequivalence. In a condition of hyperglycemia, the liver then reduced extraction of the insulin from the blood, allowing more of the glucose-responsive insulin to remain in active circulation. Greater plasma levels of the drug were correlated with increased hepatic glucose uptake (p<0.05 vs. control), non-hepatic glucose uptake (p<0.05 vs. control), and overall glucose disappearance (p<0.001 vs. control). Tracer-determined glucose levels declined in the presence of the insulin analog (p<0.05 vs. control). These results – which are extremely early-stage – support the potential of a lectin-bound molecule for smart insulin delivery, and the poster concludes that this is an approach to glucose-responsive insulin worth further consideration. That said, this very early-stage study was limited in that there’s no indication (yet) of how sensitive this lectin-bound analog will be in humans or whether it will prove clinical utility. Glucose-responsive insulin is one of the most challenging areas of diabetes research, given insulin’s narrow therapeutic range, the complexity of insulin dosing/titration, and the safety concerns that stem from releasing insulin into the bloodstream but expecting it to turn “on” and “off” automatically. We’re not giving up hope, and we’re so glad that Merck’s continued research interest in this area. Merck also has a glucose-responsive insulin candidate – MK-2640 – that finally completed its phase 1 trial in August 2016 (per its ClinicalTrials.gov page) after being delayed several times.   Whether or not the company decides to move forward with this preclinical candidate or with a phase 2 program for MK-2640 (and at this point, we’re not sure, at least in the near-term), these results will be incredibly informative to the community of researchers working on smart insulin. This includes Dr. Zhen Gu’s lab at the University of North Carolina (which recently published positive preclinical results on a smart insulin patch and was highlighted today during the ADA Pathways symposium) and many other preclinical candidates outlined in our insulin competitive landscape. Merck’s MK-2640 remains the most advanced pipeline candidate in this area, and we would of course love to see ongoing clinical development, but we’ll have to wait-and-see. Dr. Gu continues to offer big inspiration to us!

A Novel Formulation of Insulin Lispro Containing Citrate and Treprostinil Shows Significantly Faster Absorption and an Improvement in Postprandial Glucose Excursions vs. Humalog in Patients with T2DM (978P)

C Kapitza, J Leohr, R Lu, S Reddy, MA Dellva, M Matzopoulos, MP Knadler, MT Loh, T Hardy, C Kazda

In this poster, Lilly shared new data on its novel ultra-rapid insulin formulation LY900014, demonstrating that the candidate shows faster absorption and improved postprandial glucose excursions vs. Lilly’s Humalog (insulin lispro) in type 2 diabetes. Patients (n=29) were similarly randomized to either LY900014 or Humalog. LY900014 reduced the time to early half-maximal drug concentration by 23% (p<0.0001) and increased the insulin lispro area under the concentration curve vs. time from 0 to 30 min by 117% (p<0.0001) compared to Humalog. As for postprandial glucose excursions, the total excursion over the 5-hour test-meal was reduced by 105% (p<0.0001) for LY900014 vs. Humalog. Regarding tolerability and adverse events, the type 2 patient population demonstrated no differences in local tolerability and the number or severity of hypoglycemic events. As a reminder, LY900014 is Lilly’s internally-developed candidate that could begin phase 3 trials by the end of 2017. This ultra-rapid insulin has recently received more attention after the disappointing termination of Lilly’s partnership with Adocia on the phase 3-ready ultra-rapid insulin BioChaperone Lispro (see its data from ADA 2016). For more on Lilly’s discussion around the new candidate, please see our 4Q16 update.

Older Adults with Type 2 Diabetes (T2D) Experience Less Hypoglycemia when Switching to Insulin Glargine 300 U/mL (Glargine-300) vs. Other Basal Insulins (DELIVER 3 Study) (986P)

FL Zhou, F Ye, V Gupta, R Gupta, J Sung, P Berhanu, L Blonde

Sanofi presented data from the DELIVER 3 study demonstrating that switching to Toujeo (insulin glargine U300) vs. other basal insulins was associated with significantly less hypoglycemia and similar glycemic control among older patients (≥65 years) with type 2 diabetes. DELIVER 3 was a retrospective cohort analysis of de-identified patient-level EMR data in the US. The analysis included patients who switched to either Toujeo (n=468) or another basal insulin (n=1,142) between March 1, 2015 and March 31, 2016. Mean age was 71.8 years in the Toujeo group and 73.1 years in the comparator group; baseline A1c was 8.5% and 8.3% in the respective groups (both statistically significant differences). After six months, both cohorts achieved similar A1c reductions and a similar percentage of patients with A1c <7% and <8%. However, patients in the Toujeo cohort were 50% less likely to experience hypoglycemia during the follow-up period compared to the comparator cohort after adjustment for confounders (p=0.0002). The authors highlighted the fact that these results reflect Toujeo’s performance in real clinical practice, without the constraints of a randomized controlled trial. They also identified a number of limitations: the potential for selection bias, underreporting of hypoglycemia, coding errors, lack of adherence, and a lack of data on insulin dose, reasons for switching, duration of disease, and discontinuation rates. With these substantial limitations as caveats (the lack of dosing information seems particularly problematic), these results should help Sanofi build its case that Toujeo offers clinically relevant benefits over other basal insulins.

Patient-Reported Outcomes (PROs) in Insulin Degludec/Liraglutide (IDegLira) vs. Basal-Bolus (BB) Therapy in Patients (Pts) with Type 2 Diabetes (T2D): DUAL VII Trial (124-LB)

LK Billings, A Doshi, D Gouet, A Oviedo, HW Rodbard, N Tentolouris, AK Busk, A Basse, and E Jodar

This poster overviewed patient-reported outcomes (PROs) from the DUAL VII trial, demonstrating that treatment with Novo Nordisk’s Xultophy (insulin degludec/liraglutide) resulted in greater improvements related to diabetes management, treatment burden, and adherence than treatment with basal-bolus therapy. People with type 2 diabetes on insulin glargine (n=506) were randomized in an open-label setting to once-daily Xultophy for 26 weeks or to basal-bolus regimen with insulin glargine and insulin aspart. In assessing PROs, the Treatment-Related Impact Measure for Diabetes (TRIM-D) questionnaire, which consists of 28 questions across five domains, showed significant moderate significant improvements for patients on Xultophy versus basal bolus therapy in all domains, including diabetes management, treatment burden, compliance, daily life, and psychological health. After 26 weeks, total score change from baseline was +9.2 for the Xultophy group, versus +3.5 for basal bolus therapy (p<0.0001). Furthermore, the Short Form-36 version 2 questionnaire (SF-36), which consists of 36 items across eight domains, showed small improvements in all domains with Xultophy, with a significant benefit for Xultophy over basal bolus therapy in the mental health component of the survey (+2.5 vs. -0.2, p=0.0074). Additionally, after 26 treatment weeks, 85% of participants in the Xultophy arm were “very” or “extremely” willing to continue their treatment, versus only 68% of participants in the basal-bolus therapy arm. These results demonstrate that in addition to the glycemic and weight loss benefits for Xultophy demonstrated in the main DUAL VII results, this drug may have additional benefits for perception of outcomes by the patient – a major win in our eyes in terms of outcomes beyond A1c. We imagine that this improved perception of treatment outcomes with Xultophy could be influenced by better glycemic control, fewer injections, weight loss, or lower rates of hypoglycemia. However, it should be noted that this was an open-label trial, and these results could be influenced as such.

Comparable Glycemic Control, Greater Weight Loss, and Lower Hypoglycemia with Once Weekly Dulaglutide Versus Insulin Glargine, Both COmbined with Lispro, in Type 2 Diabetes and Moderate to Severe Chronic Kidney Disease (AWARD-7) (138-LB)

KR Tuttle, MC Lakshmanan, JL Gross, B Rayner, RS Busch, B Woodward, AG Zimmermann, FT Botros

The 52-week AWARD-7 trial evaluated GLP-1 agonist dulaglutide (Lilly’s Trulicity) in a head-to-head comparison with insulin glargine (Sanofi’s Lantus), both in combination with insulin lispro (Lilly’s Humalog) in patients with chronic kidney disease. Primary endpoint results of A1c change at 26 weeks were reported in this poster, as were safety findings. The trial randomized 576 patients with eGFR between 15 and 60 ml/min/1.73m² to either dulaglutide 1.5 mg, dulaglutide 0.75 mg, or titrated insulin glargine. AWARD-7 met its primary endpoint by demonstrating non-inferiority to insulin glargine in terms of A1c reduction: mean A1c reduction was 1.19% in the dulaglutide 1.5 mg group, 1.12% in the dulaglutide 0.75 mg group, and 1.13% in the insulin glargine group (baseline A1c=8.6%, p<0.001 for all comparisons to baseline). This similarity in A1c occurred in the context of increases in fasting plasma glucose (FPG) in the dulaglutide groups (+23.1 mg/dl in the dulaglutide 1.5 mg group and +17.7 mg/dl in the dulaglutide 0.75 mg group), compared to a reduction in FPG in the insulin glargine group (-19.1 mg/dl; p<0.001 compared to both dulaglutide arms). This suggests that dulaglutide has a greater effect on postprandial glucose lowering, as is expected for a GLP-1 agonist.  Similar proportions of participants achieved A1c<8% and A1c<7% in each group.

• Very notably, dulaglutide was associated with substantial weight loss and hypoglycemia benefits compared to insulin glargine. The 0.75 mg and 1.5 mg doses of dulaglutide produced mean body weight reductions of ~2 kg (~4.4 lbs) and ~3 kg (~6.6 lbs), respectively, compared to a weight increase of ~1 kg (2.2 lbs) in the insulin glargine group. Compared to insulin glargine, dulaglutide was also associated with a significantly lower rate of total hypoglycemia (p<0.001), documented symptomatic hypoglycemia (p<0.001), and nocturnal hypoglycemia (p<0.001). In addition, the higher 1.5 mg dose was associated with a lower rate of severe hypoglycemia as well (p<0.05). Participants did not wear CGM during this study, so it’s possible that these results underestimate the rate of documented symptomatic and nocturnal hypoglycemia – we would love to see greater use of CGM in these types of studies to better characterize potential hypoglycemia benefits – particularly given how easy CGM use in trials has become! Notably, these improvements in hypoglycemia occurred in the context of slightly greater increases in insulin lispro dose in the dulaglutide group compared to the insulin glargine group. From a baseline insulin lispro dose of about 0.25 U/kg, lispro dose increased to ~0.4 U/kg in the glargine group, while lispro dose increased to ~0.45 U/kg in the dulaglutide 1.5 mg group and to ~0.5 U/kg in the dulaglutide 0.75 mg group.
• Adverse events were as expected, with a higher rate of nausea, vomiting, and diarrhea in the dulaglutide-treated group. All other adverse event rates were comparable between the two groups.
• Even more intriguingly, secondary endpoint data demonstrating a potential renal-protective effect of dulaglutide on eGFR compared to insulin glargine was presented in a separate late-breaking poster (142-LB). See below for our coverage.

Dulaglutide versus Glargine, Both Combined with Lispro, Mitigated eGFR Decline in People with Type 2 Diabetes and Moderate to Severe Chronic Kidney Disease (AWARD-7) (142-LB)

KR Tuttle, MC Lakshmanan, JL Gross, B Rayner, RS Busch, AG Zimmermann, A Haupt, DB Woodward, FT Botros

This poster detailed results for a pre-specified secondary endpoint of impact on eGFR and albuminuria in the AWARD-7 trial. The AWARD-7 study team, led by Dr. Katherine Tuttle, evaluated the effect of dulaglutide (Lilly’s Trulicity) vs. insulin glargine (Sanofi’s Lantus), both in combination with insulin lispro (Lilly’s Humalog), in patients with type 2 diabetes and moderate to severe chronic kidney disease. The 52-week trial randomized 576 patients with eGFR between 15 and 60 ml/min/1.73m² to either dulaglutide 1.5 mg, dulaglutide 0.75 mg, or titrated insulin glargine. Very impressively, dulaglutide treatment appeared to mitigate further eGFR decline throughout the trial. While eGFR declined by an average of 1.9 in the insulin glargine group at 26 weeks, eGFR only declined by 0.1 and 0.4 in the 1.5 mg and 0.75 mg groups, respectively. Baseline eGFR was around 38 in all three treatment arms. The treatment difference in eGFR decline for the 1.5 mg and 0.75 mg groups was thus, respectively, 1.8 and 1.6 (p<0.05 for both comparisons to insulin glargine). By percent change from baseline, those in the insulin glargine group experienced a 7.7% decline in eGFR, while those in the dulaglutide 1.5 mg arm experienced a 0.8% decline in eGFR (p<0.05 vs. insulin glargine), and those in the dulaglutide 0.75 mg arm experienced a 3.3% decline in eGFR (p<0.05 vs. insulin glargine). Furthermore, the percent decline in eGFR in both of the dulaglutide arms was not statistically significant compared to baseline, while the decline in the insulin glargine arm was highly statistically significant (p<0.001). These differences in eGFR were driven by an apparent protective effect in patients with macroalbuminuria at baseline. On the other hand, UACR was reduced in all three treatment arms and the between-treatment difference was non-significant for this endpoint. From a safety standpoint, there were no significant differences between dulaglutide and insulin glargine for renal events of interest. Overall, these results – while only hypothesis-generating – are certainly extremely intriguing. At the very least, we can largely rest assured that dulaglutide does not increase renal risk compared to insulin glargine. Further, there appears to be a suggestion of renal benefit that we would love to see characterized further when the REWIND trial for Trulicity reports in July 2018. The LEADER and SUSTAIN 6 trials for Novo Nordisk’s GLP-1 agonists Victoza (liraglutide) and semaglutide both demonstrated a potential beneficial effect for these agents on hard renal endpoints and it would be amazing to see that corroborated in REWIND.

• Primary endpoint and safety results were presented in poster 138-LB (see above).

Qualitative Assessment of the Imapct of Insulin Degludec on Quality of Life in Patients with Type 2 Diabetes (823-P)

W Polonsky, S Lanar, N Knoble, J Weatherall, J Hakan-Bloch, E Constam, A Philis-Tsimikas, and A Marrel

This poster presented results from a prospective, non-interventional, qualitative research study demonstrating substantial quality of life (QoL) benefits following initiation of insulin degludec therapy in patients with type 2 diabetes. Twenty adults with type 2 diabetes from two sites in the US and one in Switzerland who had switched to insulin degludec from another insulin were interviewed about their experience after at least three months of use. The mean age for these patients was 66 and the mean most recent A1c was 7.8%. After qualitative analysis, four major effects of insulin degludec were identified: (i) improved physical wellbeing; (ii) increased sense of adaptability and freedom; (iii) more security, especially regarding hypoglycemia; and (4) reduced sense of burden from diabetes. Interestingly, American patients placed more weight on medical outcomes such as A1c as markers of success, whereas Swiss patients more frequently identified overall quality of life measures. Limitations of this study include the small and homogenous study population, which was mostly white, unemployed or retired, and more than 60 years old. This study may help to drive future qualitative and quantitative research to identify unique QoL benefits of diabetes medications. We feel that the benefits of next-generation therapies like Tresiba are most acutely observed on outcomes beyond A1c, such as patient-reported quality of life outcomes, and we’re glad to see Novo Nordisk take a leadership role in formally characterizing these benefits.

Ultra-Rapid Biochaperone Lispro Improves Post-Prandial Glucose Excursions Versus Insulin Lispro in a 14-day Treatment Study in Subjects with Type 1 Diabetes (964-P)

G Andersen, G Meiffren, D Lamers, A Ranson, B Alluis, M Gaudier, O Soula, T Heise, and S Bruce

Adocia’s ultra-rapid BioChaperone Lispro (BCLIS) demonstrated an accelerated absorption profile and significant reductions in postprandial glucose excursions compared with insulin lispro (Lilly’s Humalog) in people with type 1 diabetes. The randomized, monocentric, double-blind, comparator-controlled 14-day phase 1 crossover trial enrolled 36 participants (mean age 45 ± 12 years) with type 1 diabetes. Patients were randomized to receive bolus doses of either BCLIS or insulin lispro for 14 days. While in the inpatient setting for days 1-3 and 14 of the study, patients received the insulin they had been assigned to 15 minutes before, immediately before, or 15 minutes after an individualized mixed-meal, with blood samples and lispro concentrations subsequently measured. Patients continued the insulin regimens to which they had been randomized in the outpatient setting on days 4-13, and additionally self-measured plasma glucose (SMPG) levels four times daily.  BCLIS insulin had a “faster-in/faster-out” profile than insulin lispro. BCLIS dosing additionally resulted in significantly lower post-meal glycemic excursions as compared to insulin lispro  if the insulin was dosed immediately before the meal’s start or 15 minutes thereafter. Notably, postprandial glycemic excursion profiles were similar between BCLIS injected fifteen minutes after a meal’s start and insulin lispro injected immediately before a meal’s start. Mean outpatient SMPG values didn’t differ significantly BCLIS and insulin lispro. Safety profiles were also similar between the treatment groups.

Real-World Use of IDegLira Significantly Improves Glycemic Control in Patients with T2D (988-P)

H Price, B Schultes, R Prager, T Phan, B Thorsted, M Bluher

Drawing on dataset from the multi-center, retrospective EXTRA study, this poster demonstrated improvements in glycemic control, body weight, and hypoglycemia risk associated with Novo Nordisk’s Xultophy (insulin degludec/liraglutide) in a real-world setting. The EXTRA study included data (from EMRs) for 611 adult patients with type 2 diabetes in five European countries. All participant had been taking Xultophy for at least six months at time of analysis. Meeting its primary endpoint, the study found a mean A1c reduction of 0.9% six months after initiation of Xultophy (p<0.0001); similar results were observed at 3 and 12 months. A1c reductions were observed regardless of baseline therapy at time of initiation (e.g. basal insulin, oral antidiabetic drugs, GLP-1 agonists, etc.) Fasting plasma glucose also decreased by an average of 45.8 mg/dl at six months (p<0.0001). This reduction was sustained at 12 months as well (mean reduction of 44.5 mg/dl, p<0.05). Adding to these benefits, investigators also found a 0.7 kg (1.5 lbs) reduction in body weight at 6 months (p<0.05), though this varied depending on pre-study treatment regimens (weight expectedly increased with Xultophy therapy in those on just GLP-1 agonists and oral agents at baseline, for instance). The MDI at baseline subgroup was the only one that experienced significant weight loss following Xultophy initiation in this subgroup analysis – of course, subgroup analyses are notorious finicky with small sample sizes, so it’s quite likely that the weight benefits of Xultophy apply to the other subgroups as well. On the safety side of things, hypoglycemia events per patient-year decreased from 0.28 to 0.06 after Xultophy initiation — a very impressive 81% reduction (p=0.0001). Ultimately, this study shows that Xultophy is effective at improving glycemic control and reducing risk of hypoglycemia in routine clinical practice, outside of an interventional study.

Ultra-Rapid Biochaperone Lispro Improves Postprandial Blood Glucose Control versus Humalog in a 14-day Treatment Study in Subjects with Type 2 Diabetes (994-P)

T. Heise, G. Meiffren, D. Lamers, B. Kronshage, A. Ranson, B. Alluis, M. Gaudier, E. Anastassiadis, O. Soula, S. Bruce

Adocia’s ultra-rapid BioChaperone lispro (BCLIS) demonstrated an accelerated absorption profile and significant reductions in postprandial glucose control versus insulin lispro (Lilly’s Humalog) in people with type 2 diabetes. The randomized, monocentric, double-blind, comparator controlled 14-day crossover phase 1 trial enrolled 51 participants (mean age 62 ± 9 years) with type 2 diabetes. Participants were randomized to receive either individualized BCLIS or insulin lispro bolus doses with meals. On inpatient days 1-2 and 13-14, patients received the insulin to which they had been randomized with an individualized mixed-meal, after which blood samples and lispro concentrations were assessed. In the outpatient setting on days 3-12, patients continued their assigned insulin regimens and measured their plasma glucose (SMPG) levels.  BCLIS insulin had a “faster-in/faster-out” profile than insulin lispro. BCLIS additionally resulted in significant reductions in post-prandial glucose exposure for up to three hours after dosing as compared with insulin lispro.  Differences in glycemic excursions between treatments were most pronounced on days 13-14. Mean outpatient SMPG values didn’t differ significantly between BCLIS and insulin lispro, but notably, similar values were achieved with 10% lower BCLIS doses. Treatment with BCLIS was safe and well tolerated. 

SORELLA-1: Similar One-Year Efficacy and Safety in People with T1DM Using SAR342434 or Insulin Lispro in Combination with Insulin Glargine (Gla-100) (1003P)

S Garg, K Wernicke-Panten, M Rojeski, S Pierre, K Jedynasty

This poster featured one year data from the phase 3 SORELLA 1 study, demonstrating the non-inferiority of Sanofi’s SAR34233, a rapid-acting follow-on biologic to insulin lispro, to the originator product (Lilly’s Humalog) in people with type 1 diabetes, reinforcing the 26-week findings presented at ADA 2016. Developed as a rapid acting follow-on product to Humalog, SAR has an identical amino acid sequence to that of insulin lispro and a previous clamp study determined that SAR was similar in pharmacokinetic exposure and pharmacodynamics activity to insulin lispro. In the study, 507 people with type 1 diabetes were randomized to receive either a multiple daily injection regimen of SAR or insulin lispro in addition to once-daily insulin glargine. At 52 weeks, the SAR and insulin lispro groups exhibited a LS mean difference in A1c of 0.06% (95% CI: -0.084% to 0.197%), solidly indicating non-inferiority between the two drugs. In addition, both groups showed similar post-prandial glucose excursions and insulin dosages. Almost all patients reported at least one episode of hypoglycemia, but with similar incidence between the SAR and insulin lispro groups for all categories of hypoglycemia: severe (13.5% vs. 13.4%), documented symptomatic <70 mg/dl (87.3% vs. 89.8%), and asymptomatic <70 mg/dl (97.2% vs. 97.6%).Furthermore, in both SAR- and insulin lispro- treated patients, anti-insulin lispro antibody incidence levels were similar (62.5% vs. 63.1% respectively). Each treatment group had two patients who discontinued treatment due to a treatment-emergent adverse event: 54.4% of SAR-treated and 55.5% of insulin lispro-treated participants reported any adverse event. Thus, the study’s findings concluded that SAR was just as effective and well-tolerated as insulin lispro in people with type 1 diabetes.

Similar Glucose Control, Postprandial Glucose Excursions, and Safety in People with T2DM Using SAR342434 or Insulin Lispro in Combination with Insulin Glargine (Gla-100): SORELLA 2 Study (1004P)

KM Derwahl, T Bailey, K Wernicke-Panten, L Ping, and S Pierre

This poster featured initial phase 3 data from the SORELLA 2 study, demonstrating the non-inferiority of Sanofi’s SAR34233, a rapid-acting follow-on biologic to insulin lispro, to the originator product (Lilly’s Humalog) in people with type 2 diabetes. Developed as a rapid acting follow-on product to Humalog, SAR has an identical amino acid sequence to that of insulin lispro and a previous clamp study determined that SAR was similar in pharmacokinetic exposure and pharmacodynamics activity to insulin lispro. In the study, 505 people with type 2 diabetes (mean age 62 years; mean BMI 32 kg/m3; mean A1c 8%) were randomized to receive either a multiple daily injection regimen of SAR or insulin lispro in addition to once-daily insulin glargine. At 26 weeks, the SAR and insulin lispro groups exhibited a LS mean difference in A1c of -0.07% (95% CI: -0.215% to 0.067%), solidly indicating non-inferiority between the two drugs. In addition, both groups showed similar post-prandial glucose excursions and insulin dosages. Almost all patients reported at least one episode of hypoglycemia, but with similar incidence between the SAR and insulin lispro groups for all prespecified categories of hypoglycemia: severe (2.4% vs. 1.6%), documented symptomatic <70 mg/dl (60.1% vs. 66.3%), and asymptomatic <70 mg/dl (35.2% vs. 37.3%).Furthermore, in both SAR- and insulin lispro- treated patients, anti-insulin lispro antibody incidence levels were similar (38.4% vs. 36.7% respectively). Each treatment group had two patients who discontinued treatment due to a treatment-emergent adverse event: 46.6% of SAR-treated and 42.9% of insulin lispro-treated participants reported any adverse event. There was one death in the SAR arm and two deaths in the insulin lispro arm, but these were unrelated to the study drug. Thus, the study’s findings concluded that SAR was just as effective and well-tolerated as insulin lispro in people with type 2 diabetes.

Switching to Insulin Degludec Improves Glycemic Control in Patients with T2D in a Real-World Setting (1010-P)

B Schultes, N Tentolouris, S Knudsen, A Lapolla, M Eidenmueller, R Prager, T Phan, M Wolden, T Siegmund

This poster featured results from the EU-TREAT study, evaluating the real-world impact of switching to Novo Nordisk’s next-generation Tresiba (insulin degludec) on glycemic control and safety in patients with type 2 diabetes. Based on EMR records from 833 adults with type 2 diabetes, switching to insulin degludec  from other basal insulins produced improved glycemic control maintained over 12 months, as measured by A1c and fasting plasma glucose. Primary endpoint results demonstrated a moderate decline in A1c with switches to insulin degludec, from 8.4% to 7.9% (p<0.001), maintained at 12 months. Fasting plasma glucose also decreased from 178.9 mg/dl to 155.2 mg/dl (p<0.001), maintained at 12 months. Switching to insulin degludec also significantly lowered basal, prandial, and total insulin requirements. A 3.2% reduction in daily insulin requirements (p=0.006) was seen at 6 and 12 months. Body weight did not change from baseline to 6 or 12 months. Perhaps most notably, the rate ratios of overall, non-severe nocturnal, and severe hypoglycemic episodes were all significantly lower at both 6 and 12 months post-switch. At six months, switching to insulin degludec was associated with a 61% reduction in overall hypoglycemia (p<0.001), a 60% reduction in non-severe overall hypoglycemia (p<0.001), a whopping 90% reduction in non-severe nocturnal hypoglycemia (p<0.001), and a very, very impressive 92% reduction in severe hypoglycemia (p=0.004). 9% of patients discontinued insulin degludec use by 6 months, mostly due to cost, insufficient efficacy, and “other reasons.” Ultimately, this study shows that insulin degludec is effective at improving glycemic control and reducing risk of hypoglycemia in patients with type 2 diabetes in routine clinical practice, outside of an randomized, controlled trial. We applaud Novo Nordisk for undertaking these kinds of studies to better characterize the benefits of Tresiba in real-world clinical practice – at first glance, it appears that the hypoglycemia results here are even more impressive that that seen in the randomized, controlled DEVOTE and SWITCH 2 trials. While of course these types of studies will not replace RCTs, we do think they provide valuable clinical decision-making information for providers.

Switching to Insulin Degludec Reduces the Risk of Hypoglycemia in Patients with T1D in a Real-World Setting (1014-P)

T Siegmund, N Tentolouris, S Knudsen, A Lapolla, M Eidenmueller, R Prager, T Phan, M Wolden, B Schultes

Very notably, this poster highlighted results from a real-world study – using the EU-TREAT dataset – demonstrating that patients with type 1 diabetes switching to Novo Nordisk’s next-generation Tresiba (insulin degludec) from other basal insulins achieved improved glycemic control maintained over 12 months, as measured by A1c and fasting plasma glucose. What’s more, switching to insulin degludec significantly lowered basal, prandial, and total insulin requirements, while also reducing overall, severe, and non-severe nocturnal hypoglycemic episodes in the same sample. The study drew on EMR data from 1,717 adult patients with type 1 diabetes collected during the multicenter, retrospective EU-TREAT study of patients who switched to insulin degludec from another basal insulin. Results showed a small but significant decline in the primary endpoint of A1c at six months with insulin degludec, from 8.0% to 7.8% (p<0.001). Notably, this reduction was maintained at 12 months. Fasting plasma glucose also decreased from 63.4 mg/dl to 144.6 mg/dl (p<0.001), maintained at 12 months. A 10.6% reduction in daily insulin requirements (p<0.001) was observed at 6 months among those who switched to insulin degludec and the difference increased to 11.4% at 12 months. However, there was a small weight increase of +0.6 kg (1.3 lbs, p<0.001), which was stable at +0.5 kg (1.1 lbs) at 12 months. Perhaps most notably, the rate ratios of overall, non-severe nocturnal, and severe hypoglycemic episodes were all significantly lower at both six and 12 months post-switch. The six months, insulin degludec was associated with a 21% reduction in overall hypoglycemia (p<0.001), a 19% reduction in non-severe overall hypoglycemia (p=0.001), a very impressive 46% reduction in non-severe nocturnal hypoglycemia (p<0.001), and a whopping 85% reduction in severe hypoglycemia (p<0.001). These risk reductions were very similar at 12 months. In terms of safety, 5.6% of patients discontinued insulin degludec use by six months, mostly due to insufficient efficacy, cost, and “other reasons.” Ultimately, this study shows that insulin degludec is effective at improving glycemic control and reducing risk of hypoglycemia in routine clinical practice, outside of an interventional study.

Efficacy and Safety of MYL-1501D (Mylan’s Insulin Glargine) Compared with Lantus (Sanofi’s Insulin Glargine) in Patients with Type 2 Diabetes After 24 Weeks: The INSTRIDE 2 Study (1017-P)

T Blevins, A Barve, A Jacob, B Sun, and M Ankersen

Mylan’s biosimilar insulin glargine candidate, MYL-1501D, demonstrated similar efficacy and safety to Sanofi’s Lantus (insulin glargine) in people with type 2 diabetes over 24 weeks. MYL-1501D has the same amino acid sequence and formulation as Lantus. The phase 3 INSTRIDE 2 study enrolled 560 people with type 2 diabetes with A1c <9.5% who were either insulin-naïve or on once-daily Lantus and ≥two oral antidiabetic drugs (OADs) for three months before screening. Patients were randomized to either once-daily MYL-1501D (n=277) or Lantus (n=283) for 24 weeks while maintaining other OADs. After 24 weeks, MYL-1501D met its primary endpoint for non-inferiority: From a baseline A1c of 8.1%, participants in the biosimilar arm experienced a mean A1c reduction of 0.6% while those in the Lantus arm experienced a mean A1c reduction of 0.66% (A1c treatment difference of 0.06%, 95% CI: -0.10%-0.22% which crosses the line of unity). Secondary endpoints also supported the candidate’s non-inferiority vs. Lantus. There was no significant difference between groups on change in fasting plasma glucose, for example (p=0.51). On safety, both groups had similar rates of adverse events, with hypoglycemia being the most common and occurring in 27% and 23% of biosimilar-treated and Lantus-treated patients, respectively. Mylan/Biocon are expected to submit the drug candidate to the FDA “shortly,” although the date has been pushed back repeatedly according to Mylan’s 1Q17 earnings call. The candidate was submitted to the EMA in 3Q16.

Efficacy and Safety of MYL-1501D (Mylan’s Insulin Glargine) Compared with Lantus (Sanofi’s Insulin Glargine) in Patients with Type 1 Diabetes After 52 Weeks: The INSTRIDE 1 Study (1018-P)

T Blevins, A Barve, A Jacob, B Sun, and M Ankersen

This analysis of Mylan’s Biocon-partnered biosimilar insulin glargine candidate, MYL-1501D, demonstrated non-inferiority to Sanofi’s Lantus (insulin glargine) in people with type 1 diabetes (n=558). This poster presented 52-week results from INSTRIDE 1, an open-label, randomized, phase 3 study. After a six-week run-in period on Lantus, patients were randomized to either once-daily MYL-1501D (n=280) or to continue on Lantus (n=278) in addition to mealtime insulin lispro (Lilly’s Humalog). After 52 weeks, the mean change in A1c from baseline (~7.4%) was 0.21% and 0.25% for the MYL-1501D and Lantus groups, respectively, such that MYL-1501D met criteria for non-inferiority vs. Lantus (A1c treatment difference of 0.05%, 95% CI: -0.15%-0.06% which crosses the line of unity). Rates of hypoglycemia were comparable between groups, at 55% vs. 61% in the biosimilar and Lantus arms, respectively, as were rates of other adverse events. The poster concludes that Mylan’s biosimilar insulin candidate met its primary endpoint in the INSTRIDE 1 trial extension. Mylan/Biocon are expected to submit the drug candidate to the FDA “shortly,” although the date has been pushed back repeatedly according to Mylan’s 1Q17 earnings call. The candidate was submitted to the EMA in 3Q16.

Symposium: Combination Therapy in Type 2 Diabetes—Promise Delivered?

The Future of Combination Therapy in the Treatment of Type 2 Diabetes—Which Classes, Why, and When?

John Buse, MD, PhD (University of North Carolina School of Medicine, Chapel Hill, NC)

Dr. John Buse, a vocal advocate for basal insulin/GLP-1 agonist combinations from the start, suggested that these products (Novo Nordisk’s Xultophy and Sanofi’s Soliqua) should supplant insulin monotherapy as second-line treatment for type 2 diabetes. He highlighted the superior A1c-lowering efficacy, impressive weight loss, and “stunning” reductions in postprandial glucose shown across several clinical studies of Xultophy (insulin degludec/liraglutide) and Soliqua (insulin glargine/lixisenatide). What’s more, these agents are able to get a sizeable proportion of patients to A1c <7% (and ~40% of patients to A1c <6.5%) without inducing hypoglycemia – as Dr. Buse put it, in this danger zone of 0.7%-0.8% A1c-lowering below recommended targets, you’d expect to see an “exploding” increase in hypoglycemia and severe hypoglycemia, but the GLP-1 component of these compounds sidesteps the issue entirely. To further support his position on this particular combo class, Dr. Buse pointed out that the great promise of GLP-1 agonism has always been on a background of insulin. The first paper on GLP-1 in man, published in the NEJM in 1992, investigated the effects of a GLP-1 agonist on top of optimized insulin therapy. In the LEADER trial demonstrating a substantial CV benefit to liraglutide (Novo Nordisk’s Victoza), most patients were taking insulin at baseline. We echo Dr. Buse’s enthusiasm for basal insulin/GLP-1 agonist fixed-ratio combinations, and we’re eager to see greater uptake of Xultophy and Soliqua, which were only FDA-approved seven months ago (coincidentally, on the same afternoon). Pooled sales from these two products totaled $19 million in 1Q17, and we hope to see steep growth for this highly-anticipated and advanced class. We’d also love to see numbers on prescription volume, and will be keeping our fingers crossed for improved reimbursement (since we can’t expect a wide patient population to benefit from these effective new drugs if they aren’t affordable and accessible). To ADA’s credit, basal insulin/GLP-1 combos were swiftly incorporated into the 2017 Standards of Care, which were published <one month after FDA-approval of Xultophy and Soliqua. That said, particularly US-based clinicians as well as payers globally seem to be slow to move to combinations first regardless of the data showing they would benefit from this.

• “I do think there’s a role for SGLT-2 inhibitors in combination with insulin.” Dr. Buse spent part of his talk discussing this potential future direction for combination approaches in type 2 diabetes. He underscored that a majority of patients in EMPA-REG OUTCOME (Lilly/BI’s CVOT for empagliflozin, branded as Jardiance) were taking insulin at baseline, which is suggestive that these two agents can be efficacious and synergistic (though, on the other hand, only about half of participants in the CANVAS program were taking insulin at baseline). There is little guidance for patients/providers right now on how to maximize clinical benefit from a medication regimen incorporating both an SGLT-2 inhibitor and an insulin product, but Dr. Buse hopes for more language on this in upcoming iterations of professional guidelines, and so do we.
• Dr. Buse expressed early excitement for multivalent peptides, including triple combinations of GLP-1/GIP/glucagon. Preclinical investigations in animal models have produced highly-promising data so far, and Dr. Buse especially emphasized how these compounds can optimize weight loss without sacrificing glycemic control (definitely a key consideration in type 2 diabetes care). He characterized this as an up-and-coming area of combination therapy to look out for.
• Moreover, Dr. Buse called attention to a “huge opportunity” for combining a diabetes drug with a weight loss agent – he focused on canagliflozin/phentermine as an example. Phase 2 results from J&J (which markets canagliflozin as SGLT-2 inhibitor Invokana) were presented as a late-breaking poster at ADA 2016, and additional analyses were presented at this meeting. Unlike benefits to A1c, which for a combination therapy are typically less than the sum of reductions from each component monotherapy, Dr. Buse explained that benefits to weight loss can be very close to additive. Indeed, we saw additive weight loss effects for GLP-1 agonist/SGLT-2 inhibitor co-administration in DURATION-8 –  though Dr. Buse was less positive about the glycemic effects of the combination (see below). It’s unclear at the moment whether J&J will move forward with phase 3 studies of canagliflozin/ phentermine, but with such unequivocal support from a thought leader like Dr. Buse, we see a strong case for further clinical development.
• Lastly, Dr. Buse shared some skepticism on GLP-1 agonist/SGLT-2 inhibitor combination approaches. While results from DURATION-8 investigating AZ’s Bydureon (exenatide once-weekly) alongside Farxiga (dapagliflozin) were positive, Dr. Buse emphasized the sub-additive benefits to A1c – “I had hoped for more.” He mentioned the differential effects on glucagon from SGLT-2 inhibitors vs. GLP-1 agonists as one potential concern. On the other hand, Dr. Buse acknowledged that this area of combination treatment holds possibility for aggregate CV benefits. While topline results from the EXSCEL CVOT for exenatide were neutral, other GLP-1 agonists like liraglutide and semaglutide have shown significant cardioprotection, and we’ve now seen CV superiority vs. placebo for two SGLT-2 inhibitors as well – empagliflozin and canagliflozin. Dr. Buse concluded: “Before rushing off and building up GLP-1/SGLT-2 as the clear savior of all patients with diabetes and CV disease, we need to be cautious about understanding this combination better.”

Symposium: Dealing with the Rising Costs of Insulin – An Active Dialogue

The Rising Costs of Insulin – Introduction and Historical Perspective

Kasia Lipska, MD (Yale School of Medicine, New Haven, CT)

Dr. Kasia Lipska opened this highly-anticipated symposium on insulin costs with a look at the history of insulin development and pricing. Unsurprisingly, given her somewhat controversial previous commentary on insulin pricing, Dr. Lipska took a relatively critical stance on the value of modern insulin analogs, describing what she termed “the paradox of incremental innovation.” While the benefits are of course incremental for some, they are quite striking for others, and it was disappointing to hear this dismissive, one-size-fits-all language. She acknowledged that substantial and important advances have been made in insulin therapy – making insulin much safer and “more convenient” – since its discovery in 1922, but pointed out that these improvements have occurred in a stepwise manner, with new patents accompanying each advance. (She didn’t give another view on how she would suggest advances take place.) Further, she noted that, with the arrival of newer insulin, older insulins often largely became obsolete and disappeared from the market in high-income countries like US in particular. She highlighted this as the “paradox,” as generally older products create a market for generics, which largely has not happened in the insulin field – though this may be changing with the arrival of Lilly/BI’s biosimilar insulin glargine Basaglar (and upcoming biosimilars from Merck and Mylan/Biocon). All in all, she posed the question, “Was each incremental innovation worth the price that we pay today?” While we certainly sympathize with the point that insulin pricing is a major problem for many patients (as, we would add, prices for heart attacks, strokes, dialysis etc), it is not our sense that innovation in insulin is the main driver of increasing costs (compared to the complex PBM/rebate negotiation system, etc.) and we certainly would not term substantial benefits in hypoglycemia and ease-of-dosing an “incremental” improvement in quality of life for many patients. That said, we recognize that insulin analogs may be out of reach for some patients in the current healthcare system and, to that end, we appreciated Dr. Lipska highlighting her recent JAMA viewpoint (co-authored with Drs. Irl Hirsch and Matthew Riddle) on practical tips for physicians on human insulin therapy in patients with type 2 diabetes. We also appreciated Dr. Lipska’s acknowledgement that human insulin certainly is not a solution for everyone and that modern insulins are “definitely better” than older versions from a pure clinical standpoint (which presumably she would acknowledge is important – the clinical viewpoint). Finally, Dr. Lipska concluded her presentation by acknowledging the complexity of contributors to insulin pricing and highlighted several remaining questions: (i) Who are the other players contributing to rising insulin prices?; (ii) What else can clinicians do to keep costs down?; and (iii) What are the potential policy solutions? She didn’t say what part of her work would be addressing this, but we look forward to her solutions.

Questions and Answers

Q: The average wholesale price (AWP) shown in that diagram – why is there so little transparency in that?

A: Some say “AWP” also stands for “Ain’t What’s Paid.” It’s not the real price of the insulin. Pharma companies tell us that the actual net price of insulin has either stayed the same or hasn’t increased as well. The gap between the two has risen, and part of that is because of rebating and discounts for insurers and PBMs in this process. You’re right, we need more transparency to see if we can judge it as far as it’s not clear where money changes hands in this system. (Editor’s note – it’s not clear if Dr. Lipska has looked at annual reports for these organizations – for the last several years, this information has been publicly report by Novo Nordisk and Lilly and others).

Understanding the Players in the Rising Costs of Insulin

Alan Carter, PharmD (MRIGlobal, Kansas City, MO)

Pharmacist Dr. Alan Carter emphasized the complex “cast” of players in the issue of insulin pricing, including suppliers of raw materials, manufacturers pharmaceutical wholesalers, pharmacies, prescribers, and people with diabetes. Overall, however, he underscored in great detail that insulin is an extremely complex process, with safety and quality assurance standards largely in the court of individual manufacturers. As a result, trust in insulin manufacturers is paramount and quality assurance trumps price. He suggested that new policies like Medicare Part D and the ACA had the unintended consequences of increasing PBM leverage, which is one of the main drivers of increasing costs. At the same time, Dr. Carter argued that it will take all stakeholders – “a village” – to safety and effectively lower insulin costs without sacrificing safety and quality.

Clinical Decision-Making in a Cost-Conscious Era

David Robbins, MD (University of Kansas, Kansas City, KS)

Dr. David Robbins outlined several opportunities for healthcare providers, patients, the ADA, the government, pharmaceutical companies, and all of us to impact insulin, drug, and healthcare pricing. For the field as a whole, Dr. Robbins asked all the various stakeholders to stop oversimplifying the issue of drug pricing and to share the blame, rather than point fingers. Further, the formation of partnerships to tackle this problem are crucial. He also emphasized the need to healthy, educated, and fair critics, while recognizing that we are all subject to bias. To that end, he emphasized that “new” is not always better. And finally, he called upon attendees to always advocate for their patients – hear hear!

• For healthcare providers, Dr. Robbins emphasized the need to be a “tough, but fair, critic.” He suggested that conflicts of interest and bias is rampant in among prescribers. Underscoring his point, he cited a study that found every additional $13 payment or gift from a pharmaceutical company to a prescriber was associated keeping a patient on a particular drug for an additional 107 days (p<0.001). He emphasized that the healthcare field has a whole has to take a hard look at conflicts of interest and be honest with themselves about how this may bias clinical care. To help make better decisions on which diabetes drugs to actually prescribe, Dr. Robbins highlighted the importance of healthcare providers asking patients about their individual resources. Dr. Robbins also called upon healthcare providers to demand better guidelines and rigorous comparisons of new vs. old medications and tools. Additionally, more emphasis on the prevention and early reversal of type 2 diabetes is needed. Finally, Dr. Robbins suggested that healthcare providers have an obligation to spend time volunteering care in free clinics.
• For patients, Dr. Robbins highlighted the benefits of being an informed consumer. Dr. Robbins asked patients to understand the benefits of drugs and ask their providers if the branded medications are really better than lower-cost generics. Further, in cases where insurance coverage may be denied, Dr. Robbins called on patients to doggedly ask the insurance companies for the reason behind the denial, rather than just accepting it.
• For the ADA, Dr. Robbins wished for greater transparency on the organization’s funding sources and the inclusion of such disclosures on the widely-used ADA diabetes guidelines. Dr. Robbins acknowledged that pharmaceutical funding is critical to support the wide breadth of programs that the ADA is engaged in, but he suggested that separating ADA guideline and opinion statements from such funding. He also asked the ADA to support comparative effectiveness studies of different medications – including both branded and generic options – to help providers with difficult clinical decision-making. Finally, Dr. Robbins argued that the ADA should not taking advertising from pharmaceutical companies on its website or other materials.
• From a regulatory standpoint, Dr. Robbins argued that the FDA and other government agencies should set a higher bar for new diabetes drugs, demonstrating improvements over standard of care rather than just demonstrating efficacy compared to placebo. As he put it, the government has dual obligations of protecting and also guiding the consumer.
• Dr. Robbins also highlighted several opportunities for pharmaceutical companies. In particular, he asked manufacturers to demonstrate that new drugs are cost-effective and to expand and simply safety net programs for expensive and critical drugs. He also suggested that companies stop fighting Medicare’s efforts to employ competitive bidding (though, in our view, competitive bidding processes must also be accompanied by rigorous quality assurance standards). Finally, Dr. Robbins emphasized that pharmaceutical companies need to do a better job of communicating their narrative and “what they do right.” For instance, he emphasized that these companies employ truly dedicated people, the USA leads the world in discovery and innovation, and these companies often return reasonable profit margins (which the exception of predatory companies like Turing and Valeant). All in all, Dr. Robbins suggested that manufacturers need to do a better job of communicating the high cost of drug R&D.

Paving the Way Forward

Robert Ratner, MD (Georgetown University School of Medicine, Washington, DC)

Answering the question “What’s the solution to high insulin prices?,” former ADA Chief Scientific and Medical Officer Dr. Robert Ratner stated that there is only one real solution: “Someone has to make less money.” He emphasized that the system of insulin pricing/coverage/rebating is extremely complicated and that a lack of transparency makes it difficult to understand where the bulk of the money is going. That said, Dr. Ratner noted that rebates to pharmacy benefits managers (PBMs) rose substantially from $67 billion in 2013 to a whopping $106 billion in 2015. While acknowledging that an appropriate level of profit from insulin supports R&D and prices in the US subsidize insulin in low- and middle-income countries, Dr. Ratner stated to great applause, “The issue of middlemen with no added value increasing expenditures is something we can get rid of without having any downward pressure on insulin pricing elsewhere” – hear hear! Dr. Ratner views free market competition mechanisms as the most likely to be successful in driving insulin pricing reform. He acknowledged that the very first biosimilar insulin glargine – Lilly/BI’s Basaglar – has not been discounted quite as much as some had hoped (in the US, the follow-on biologic is discounted about 15% relative to originator Lantus). On the other hand, he underscored that we typically must wait for two or more generics to see price driven down, and Dr. Ratner was fairly optimistic on the future launch of additional biosimilars given that new FDA commissioner Dr. Scott Gottlieb has publicly highlighted simplification of the biosimilar regulatory process as one of his goals. Even with the current, rather complicated process, Merck has already submitted a biosimilar insulin glargine formulation and Mylan/Biocon are planning to submit their own formulation shortly. Dr. Ratner also sees greater proliferation of direct-to-consumer programs as promising – he highlighted Walmart’s $26/vial human insulin as an excellent example of how the complex insurance/PBM/rebate system can be bypassed entirely to bring insulin directly to patients at a lower cost. We think that the Blink Health and InsideRx direct discount programs are a good example of this principle as well, though the prices for medications through these programs are admittedly still much higher than that of Walmart insulin. Most promising in Dr. Ratner’s view, however, are the recent proliferation of lawsuits accusing insulin manufacturers, payers, and PBMs of price-fixing in insulin. While he reserved judgement on whether any of these lawsuits had merit, he pointed out that they will force transparency in this opaque field by forcing various stakeholders to disclose their contractual agreements as part of discovery. We think it’s highly unlikely that any actual price-fixing is occurring and, while we wholeheartedly agree with the need for transparency, we wish it wouldn’t take several high-profile lawsuits to encourage companies to disclose their financial agreements. We certainly believe voluntary disclosures would generate more goodwill, while these lawsuits that only further exacerbating the public furor over drug pricing. The “story” has spun out of control in many ways and we continue to hope that manufacturers and other stakeholders will take the initiative to address these concerns head-on – without being pushed by external forces. Some progress has been made in recent months, but there is still much more room to help relieve the financial burden of diabetes care for patients.

• On the other hand, Dr. Ratner was less optimistic about the potential for legislative or regulatory controls to offer near-term relief on insulin pricing. He noted that there has been significant discussion among politicians and in legislature (both at the state and the national level) on potential policy solutions to the issue of high drug costs. He highlighted proposals to allow Medicare Part D to negotiate with manufacturers, government-imposed price controls, and challenges to “pay for delay” tactics, but ultimately emphasized that the legislative process can be incredibly slow. On the regulatory front, he suggested that some of the proposals floating around could have unintended, negative consequences from a global perspective. For instance, he noted that calls to allow the importation of drugs from other counties have become popular in some circles and that this would actually be possible within the current purview of the FDA, without need for legislative change. That said, Dr. Ratner pointed out that the last four FDA commissioners (including Dr. Gottlieb) has come out “categorically against” this idea. Further, Dr. Ratner suggested that cross-border importation of insulin would actually incentivize companies to only sell insulin in companies that can command a higher price, like the US, and potentially create insulin shortages in other countries.

Symposium: ADA Pathway to Stop Diabetes Symposium

Responsive Vesicles Integrated with Transcutaneous Patches for Glucose-Mediated Insulin Delivery

Zhen Gu, PhD (University of North Carolina, Chapel Hill, NC)

Echoing his talk at the JDRF Mission Summit in January, Dr. Zhen Gu discussed several approaches to glucose-responsive insulin delivery that his iMedication lab is researching. Two projects – the microgel and nano-network approaches – use the enzyme glucose oxidase to convert glucose to gluconic acid and create an acidic environment that activates the release of insulin. While these approaches have shown some positive effects in preclinical models, Dr. Gu explained that response speed has been a challenge, as the body’s buffering ability makes it difficult to immediately generate an acidic environment. Therefore, the lab is also exploring a hypoxia-sensitive insulin patch that releases insulin when oxygen levels fall (both glucose and oxygen are consumed in the glucose oxidase reaction). Finally, Dr. Gu mentioned his lab’s preliminary efforts to use red blood cells for smart insulin delivery: the cells are coated with modified insulin that detaches in response to high glucose. In addition to speed, other key challenges that Dr. Gu cited include the risk of hypoglycemia, ease of administration, and biocompatibility.

Symposium: What’s New in Insulin-Related Therapy?

Old Problems, New Solutions – Insulin Management Through Innovation

Lori Berard (WRHA Health Sciences Centre Diabetes Research Group, Winnipeg, CA)

Ms. Lori Berard’s talk on non-pharmacological innovations in insulin initiation and titration centered on a singular theme: “We’ve had 100 years of insulin, but there are still a LOT of problems we deal with on a day-to-day basis.” Ms. Berard set the stage for this topic by reviewing the classic barriers to insulin therapy (e.g., fear of needles, hypoglycemia, complications, weight gain, etc.), noting that while the field has addressed many of these limitations, there is still much left to do. She acknowledged that we’ve done a fairly good job at ‘figuring out’ insulin therapy in people with type 1 diabetes, attributing this to the fact that these patients are often seen by specialists accustomed to prescribing insulin. Meanwhile, she argued that primary care physicians are left with the responsibility of treating a growing type 2 population and that it is here that we are failing our patients (especially in terms of initiation). In particular, Ms. Berard shared her assessment that many PCPs lack confidence in prescribing insulin to type 2s (leading to delayed starts) and that even when we do give insulin, “we’re not good at supporting patients beyond the initial prescription.” More broadly, she pointed out that this is a population in which perceived disease severity is often lacking and in which there is a very strong perception of failure. She argued that these factors are all the more reason to focus future innovation on our prescribers and equipping them with better tools to prescribe/titrate insulin and communicate with their patients – e.g., automated insulin titration, shared decision-making systems. As she summarized playfully at the end, “If we could just help the people who help patients get to goal, then we’d be in a better place.” Agreed!

Corporate Symposium: The Physiologic and Mechanistic Rationale for Achieving HbA1c Target Goals with Basal Insulin in Vulnerable Patients with Type 2 Diabetes (Sponsored by Sanofi)

The Physiologic Rationale for Optimizing HbA1c Target Goal Attainment with Basal Insulin

Vivian Fonseca, MD (Tulane University School of Medicine, New Orleans, LA)

There are currently 29 million people with diabetes and 1.9 million new cases per year, and approximately 50% of these individuals are unable to achieve glycemic targets (A1c ≤7%). Dr. Vivian Fonseca opened his presentation with these hard-to-stomach stats, and continued on to outline multiple reasons that keep patients from getting to goal: Namely, the complex pathophysiology of type 2 diabetes and the progressive decline in beta cell function. Insulin therapy is necessary in type 2 diabetes because it is sometimes the sole therapeutic agent that can help patients achieve glycemic goals. Furthermore, insulin is safe when properly administered, and has proven effectiveness. Patients are often reluctant at first to start insulin, but delaying insulin therapy can be harmful later on. Dr. Fonseca argued that it’s important to start insulin at a lower A1c, because it is more effective at reducing A1c ≤7% when the baseline level is lower. In order to find an insulin that works best for each individual, important factors to consider include the absolute A1c reduction rate, amount of hypoglycemia, level of complexity, and insulin titration and doses. Dr. Fonseca concluded by re-emphasizing the importance of using basal insulin as a therapeutic option early on in individuals with type 2 diabetes.

Optimizing Glycemic Control While Mitigating Hypoglycemic Risk in Challenging Patients with T2D

Pablo Mora, MD (Dallas Diabetes Research Center, Dallas, TX)

Dr. Pablo Mora discussed the role of basal insulin and walked attendees through the barriers to insulin use in real-world clinical practice. He opened by appreciating patient/provider concerns related to hypoglycemia, weight gain, and the stigma associated with insulin use. That said, Dr. Mora emphasized that intensive glucose lowering is safe and carries the greatest lifetime benefit when initiated early in the course of diabetes. He turned to data on the most advanced basal insulin products on the market, including Novo Nordisk’s Tresiba (insulin degludec) and Sanofi’s Toujeo (insulin glargine U300). Specifically, Dr. Mora discussed the molecular nature of the degludec and glargine insulin analogues and reviewed positive results from the SWITCH studies and the EDITION clinical program. He highlighted that these newer basal insulins offer less variability, longer duration of action, easy and safe titration methods, and improved safety outcomes (on the hypoglycemia front, on the CV front). Dr. Mora concluded that the PK/PD profiles of new insulin therapies and the advanced features of new insulin delivery devices have made insulin therapy significantly more user-friendly.

All Basal Insulins Are Not Created Equal: Comparative PK/PD, Efficacy, Side-Effect (Hypoglycemia), and Safety Profiles for Established and New Longer-Acting Basal Insulins

Guillermo Umpierrez, MD (Emory University, Atlanta, GA)

For type 2 diabetes, Dr. Guillermo Umpierrez advocated that insulin should be started in patients with hyperglycemic emergencies, high baseline A1c, or when combination oral or injectable agents are no longer effective. For these patients, there are many different basal insulin products available, at different doses and different dosing frequencies. Many of these products have similar effectiveness, but Dr. Umpierrez described how patients will make their choice based on personal preferences: It comes down to how they relatively weigh injection frequency, lifestyle factors, flexibility of regimen, level of support available, and cost. Moreover, when basal insulin is no longer sufficient, patients may add bolus insulin in order to improve glycemic control, which comes with its own set of options. Regardless of the type of insulin used, the addition basal insulin to a diabetes treatment regimen helps between 40-50% of patients reach A1c goals, and adding mealtime insulin helps between 50-60% of patients achieve A1c goals, according to Dr. Umpierrez. Combination therapy using insulin and incretin agents is especially effective in helping individuals with type 2 diabetes improve glycemic control and reduce hypoglycemia. We loved this mention of fixed-ratio GLP-1/basal insulin combos, including Sanofi’s Soliqua (lixisenatide/insulin glargine) and Novo Nordisk’s Xultophy (liraglutide/insulin degludec).

Modifying Insulin Therapy in Complex and Vulnerable Patients: Practical Approaches for Switching to a Physiologic, Basal Insulin Formulation

Juan Frias, MD (National Research Institute, Los Angeles, CA)

Dr. Juan Frias delivered a clinician-focused presentation on practical considerations for the use of basal insulin. Acknowledging the many barriers that lead to the delay of insulin therapy, Dr. Frias highlighted the advantages of newer insulin delivery devices. Specifically, he noted that insulin pens are associated with greater accuracy, reduced hypoglycemia, and improved patient adherence. He also gave high praise to insulin glargine U300 (Sanofi’s Toujeo), sharing that compared to the U100 formulation of insulin glargine (Sanofi’s Lantus), Toujeo has a more constant and prolonged PK/PD profile, lower glycemic variability, and lower hypoglycemia risk. In discussing practical approaches for Toujeo use, Dr. Frias suggested titrating doses based on self-monitored fasting plasma glucose results, no more frequently than every three-four days. In addition, he shared insights on the clinical use of insulin degludec (Novo Nordisk’s Tresiba), advising attendees on recommended starting dose, dose increases, and patient education on missed doses. In conclusion, Dr. Frias positioned basal insulin as the gold standard of injectable therapy.

Questions and Answers

Q: In what populations do you use Sanofi’s Lantus (insulin glargine U100)?

Dr. Umpierrez: I very seldom use glargine U100, except in type 1 diabetes at very low doses. In general, this is once-daily.

Q: How do you overcome socioeconomic barriers?

Dr. Frias: I hear about this a lot from my patients – 90% are Latino. They’ve seen their relatives have severe problems with diabetes and they associate that with insulin. A lot of this can be solved through education. It helps to show them the needle and say we can always stop if needed.

Dr. Mora: The Hispanic population gets really worried when we talk about multiple injections a day. So giving the story that insulin is good and safe and only needs to be injected once per day can help.

Dr. Fonseca: And giving the first injection sometimes helps. They realize that it doesn’t hurt so bad.

Dr. Frias: Also, sometimes adding a GLP-1 agonist to basal-bolus therapy is nice.

Dr. Mora: In my experience, the level of comfort to initiate GLP-1 therapy is not quite there yet. For both the clinician and the patient.

Q: What are the options for GLP-1 agonists in patients with an eGFR of 48 ml/min/1.73m²?

Dr. Fonseca: There isn’t much of a concern. These agents are not toxic to the kidney. There may be some nausea, vomiting, and dehydration. These side-effects can be more problematic for people with lower eGFR. But in general, I don’t think that’s much of a concern.

Dr. Umpierrez: The study with liraglutide showed that the GLP-1 agonist agent can be used safely on eGFRs as low as 30 ml/min/1.73m².

Q: Thoughts on the hypoglycemic profile of ultra-concentrated, U500 insulin compared to other formulations of insulin glargine?

Dr. Umpierrez: I have very little experience with U500. I don’t believe in it a lot, so I don’t use it.

Dr. Fonseca: I use it a fair amount in these people who have severe insulin resistance. So you don’t get much hypoglycemia. But when you get them under better control, it could be a problem. I can get by without using basal. I give it three times/day, sometimes with a GLP-1 agonist.

Dr. Mora: I would have a bit of caution with U500 in that it accumulates at the end of the day, so it’s good to back off at the end of the day.

Corporate Symposium: Optimizing Comprehensive Glycemic Management in Challenging Patients with Type 2 Diabetes (Sponsored by Sanofi)

Vanita Aroda, MD (Georgetown University School of Medicine, Hyattsville, MD), Lawrence Blonde, MD (Ochsner Medical Center, New Orleans, LA), Vivian Fonseca, MD (Tulane University Health Sciences Center, New Orleans, LA), and Juan Frias, MD (UCLA, Los Angeles, CA)

This Sanofi-sponsored corporate symposium highlighted the potential of basal insulin/GLP-1 agonist fixed-dose combinations as an optimal therapeutic options for patients not achieving their goals on basal insulin alone. Dr. Vivian Fonseca kicked off the symposium with an overview of current treatment options, the need for therapies that help patients achieve glycemic goals with minimal hypoglycemia and weight gain, and the importance of the patient-oriented perspective on minimizing injections and daily burdens of therapies. Dr. Vanita Aroda then discussed the importance of addressing postprandial glucose (PPG) as an integral part of treatment to lower A1c. PPG may also be tied to cardiovascular risk, although trial data has been mixed. She examined both short- and long-acting GLP-1 agonists and their differing effects on PPG, finding that short-acting GLP-1 agonists like exenatide and lixisenatide flattened PPG glucose levels significantly while long-acting liraglutide only showed some suppression of PPG. Dr. Blonde then led a review of the treatment options in type 2 diabetes and the use of basal insulin as the first choice injectable therapy recommended by the ADA and AACE. Interestingly, in a series of five studies investigating basal insulin as the first injectable, GLP-1 agonists were found to be more effective in A1c reduction and additionally helped with weight loss. Dr. Blonde also reviewed the impact of hypoglycemia in insulin use, which is a key challenge for patients and a common reason cited for patients who choose to discontinue insulin. Newer insulins like Novo Nordisk’s Tresiba (insulin degludec) or Sanofi’s Toujeo (insulin glargine U300) are associated with similar A1c and weight reductions as older insulins but also have the additional benefits of lowering the risk for both nocturnal and severe hypoglycemia, as demonstrated  in trials like SWITCH 2 and EDITION 1, 2, and 3. However, Dr. Blonde pointed out that many patients will not attain or maintain target glycemia with basal insulin alone, and there are further strategies for intensification depending on the patient’s profile. When on the lower end of the A1c spectrum, hyperglycemia may be driven more by PPG and can be addressed by combination injectable therapy. To conclude the symposium, Dr. Juan Frias knitted everything together with a broad overview of the complementary mechanisms of action between basal insulin and GLP-1 agonists on insulin release, glucose uptake, glucose production, glucagon secretion, and gastric emptying. The two major fixed-dose combinations – Sanofi’s Soliqua (insulin glargine/lixisenatide) and Novo Nordisk’s Xultophy (insulin degludec/liraglutide) - are approved in the US for patients suboptimally controlled on any basal insulin or lixisenatide and/or liraglutide in combination with any oral medication. However, in Europe these agents have more expansive labels approved as the first injectable agent. The benefits of a fixed-ratio combination compared to individual components is compelling – improved glycemic control, a body weight benefit, no increase hypoglycemia, and reduced GI side effects.

Questions and Answers

Q: Some patients stop responding to GLP-1 agonists. Can you explain why this happens and how to address it?

Dr. Fonseca: Some people just stop taking the medication and you need to have a frank discussion about that. Secondly, you wonder about the development of antibodies, particularly with exenatide. Neutralizing antibodies are not that common in GLP-1 agonists except in exenatide. In that case, you can stop the drug and switch to another GLP-1 agonist and see what happens. Thirdly, it is possible to use GLP-1 agonists inappropriately because the patient lacks insulin. If you’re insulin deficient, nothing is going to work.

Dr. Frias: Secondary failure is the nature of type 2 diabetes management. At some point you reach an equilibrium or your diabetes progresses.

Q: It seems like we are giving our patients all of these drugs, but not reaching our goals. What else can you do?

Dr. Aroda: We keep treating to failure and we need to prevent that.

Dr. Blonde: There are studies that show earlier treatment with combinations of agents may produce more durable reductions in A1c. It would be interesting to do a study in coformulations that looks at simultaneous versus sequential therapy. There are studies that suggest simultaneous is better than sequential.

Q: You use U500, the maximal amount of insulin. What do you do when someone needs more than that?

Dr. Aroda: Well you’ve got to treat the patient. If they need more insulin then give it to them, but you should also be asking why the maximum amount of basal is not working. And maybe you should consider bariatric surgery or something of the like to handle this.

Q:  The ideal combo would be U300 and lixisenatide for a lot of patients. Why wouldn’t you use this?

Dr. Fonseca: Well the simple answer is that you can’t give test two experimental agents at the same time and these two drugs were in the experimental process at the same time so you can’t do that right now. The FDA won’t let you do that. But in the future you may see that there are trials around this and while I don’t like to predict the future often, you could see this coming sometime soon. 

Product Theaters

Diabetes – Treatment and Management (Presented by Sanofi)

Bruce Bode, MD (Emory University, Atlanta, GA)

Dr. Bruce Bode presented a product theater focused on Sanofi’s Toujeo (U300 insulin glargine), highlighting its gradual and stable insulin release, A1c reductions, and safety profile. Dr. Bode first opened by stressing the complexity of type 2 diabetes treatment and the ADA 2017 guidelines’ various therapeutic options. He also stressed the importance of discussing insulin early in people with diabetes, highlighting the progressive nature of the disease and the need to dispel negative myths of the progression to insulin as an indicator of failure. Moving to present Toujeo, Dr. Bode emphasized its reduced injection volume, smaller precipitate, and gradual insulin release. He shared much of the clinical data from the EDITION study program, dosing recommendations, safety information, and warnings and precautions. Closing the product theater, Dr. Bode additionally mentioned the accompanying COACH support program and Sanofi’s co-pay card.

Questions and Answers

Q: Any differences between hypoglycemia for Lantus vs. Toujeo?

A: I was a researcher in several of these trials. EDITION 1 and 2 showed significant reductions in hypo. In EDITION 3 and 4, there was a trend toward hypoglycemia but it was not significant.

Q: What’s your experience of Toujeo in practice?

A: It’s very easy to get. I rarely get denials up until the launch of the new insulin from Lilly. Basaglar and Tresiba are covered. And coupons can be used for Part D.

Q: What’s the accuracy and variability of the pen device?

A: It’s more precise than giving a syringe. That’s been true since pens have been developed. Pens’ accuracy is quite accurate.

Q: What would you do with other oral agents?

A: Always stop SFUs – it impairs the ability to titrate insulin without causing hypoglycemia. Always keep metformin, if the patient can tolerate it. I’ll also generally keep GLP-1s and SGLT-2s.

Q: When should I change Lantus to Toujeo?

A: Based on the label, when you are not getting control at night, especially for type 1 diabetes. If you’re not yet at goal, Toujeo’s a good choice.

Clinical Data Review – Comparing the Safety and Efficacy of Two Once-Daily Basal Insulins in Patients with Type 1 and Type 2 Diabetes

Carol Wysham, MD (University of Washington, Spokane, WA)

In this Novo Nordisk-sponsored product theater, Dr. Carol Wysham reviewed the data from the SWITCH 1 and SWITCH 2 trials demonstrating significant reductions in hypoglycemia with Novo Nordisk’s Tresiba (insulin degludec) vs. Sanofi’s Lantus (insulin glargine). In SWITCH 1, Tresiba was associated with 11% less severe and symptomatic hypoglycemia, 36% less nocturnal hypoglycemia, and 35% less severe hypoglycemia than Lantus in patients with type 1 diabetes. In SWITCH 2, Tresiba was associated with 30% less severe and symptomatic hypoglycemia and 42% less nocturnal hypoglycemia than Lantus in patients with type 2 diabetes. Novo Nordisk announced in its 1Q17 update in May that the EMA has approved a label update for Tresiba based on the SWITCH results; a corresponding FDA decision is expected by September 2017. Novo Nordisk has also submitted data from DEVOTE (which demonstrated an impressive 40% reduction in severe hypoglycemia and 53% reduction in nocturnal severe hypoglycemia with Tresiba compared to Lantus) to the FDA and the EMA.  Novo Nordisk is clearly hoping that these label additions will help give Tresiba an edge over its most direct competitor, Sanofi’s Toujeo (U300 insulin glargine), which has no hypoglycemia claim in its label.

Questions and Answers

Q: Why is Tresiba not recommended in pediatric patients needing less than five units?

A: It wasn’t studied and I assume you couldn’t use that pen for that amount of insulin.

Q: Why was the fasting plasma glucose goal so low?

A: Those were the goals used in several other basal insulin studies and they found that it was a safe goal. Almost all the trials that targeted a glucose <100 mg/dl never achieved a level below 115-120 mg/dl, so the goal was to get fasting glucose more consistent.

Q: Why were the results taken at the end of the maintenance period?

A: We were looking not at what might happen during the time when we were rapidly changing the dose but assuming that during the maintenance period the dose would be fairly consistent, so the groups would be most comparable.

Q: What was the conversion for patients with type 2 diabetes on BID basal insulin?

A: Patients already on once-daily basal insulin were converted unit per unit. If they were on twice-daily insulin, the recommendation was to decrease it, although it was individualized by A1c and frequency of hypoglycemia.

Q: Why did the Tresiba trials not show A1c superiority to glargine?

A: Remember that the original trials of glargine against NPH didn’t show superiority either. The investigators had guidelines and were told to titrate to get to goal. They made the decision on whether to titrate based on strict criteria, so this result was expected. In order for hypoglycemia rates to be compared, you had to have equivalent A1c reductions. Otherwise you couldn’t really meet the FDA requirements for understanding hypoglycemia rates.

Q: Was there any difference in the types of oral medications in SWITCH 2?

A: No, the patients were pretty well balanced.

Q: In SWITCH 1, was there any difference in the timing of injections?

A: The recommendation was to give it at the same time every day but the investigators were given some leeway. Because they were comparing Tresiba to glargine, they were asked to give it at the same time every day.

Q: Was there a difference in dosage?

A: In SWITCH 1, in order to achieve the same A1c, a 3% lower dose of Tresiba was required. In SWITCH 2 it was a 4% lower dose.

GLP-1 Agonists

Symposium: Update on Cardiovascular Outcomes Trials (CVOTs)

Cardiovascular Outcomes with Semaglutide in Subjects with Type 2 Diabetes Mellitus (SUSTAIN 6)

Tina Vilsbøll, MD (University of Copenhagen, Copenhagen, Denmark)

Very notably, Dr. Tina Vilsbøll presented brand-new analyses of the SUSTAIN 6 cardiovascular outcomes trial (CVOT) for Novo Nordisk’s once-weekly injectable GLP-1 agonist semaglutide, offering a deeper dive into the worrisome 76% increased risk for retinopathy complications observed in the trial. In SUSTAIN 6 (n=3,297), diabetic retinopathy complications were a pre-defined and adjudicated composite endpoint consisting of four events, two related to diagnosis (vitreous hemorrhage and onset of diabetes-related blindness defined as visual acuity of 20/200) and two related to treatment (retinal photocoagulation and intravitreal agents). Overall, 50 participants in the semaglutide arm experience retinopathy complications (an event rate of 3%), compared to 29 in the placebo arm (1.8% event rate). By event type, 22 participants taking semaglutide required retinal photocoagulation (1.3%, vs. 14 on placebo [0.9%]), 10 taking semaglutide required intravitreal agents (0.6%, vs. 7 on placebo [0.4%]), 13 taking semaglutide experienced vitreous hemorrhage (0.7%, vs. 7 on placebo [0.4%]), and 5 taking semaglutide experienced new-onset diabetes-related blindness (0.3%, vs. 1 on placebo [0.1%]). Importantly, there were significant differences in the patient population that experienced retinopathy complications – in both the semaglutide and placebo arms (n=79 total) and the overall SUSTAIN 6 population. Average diabetes duration in this population was 17.5 years (vs. 13.9 years overall), mean baseline A1c was 9.4% (vs. 8.7% overall), and 76% were treated with insulin at baseline (vs. 58% in the general population). Further, and perhaps most importantly, the majority of patients who experienced complications had a history of retinopathy at baseline – 84% has a history of diabetic retinopathy (vs. 29% in the general population), 29% had a history of medical retinopathy (vs. 6% in general population), and 18% had a history of both proliferative retinopathy and treatment with laser therapy or intravitreal agents (vs. 3% in the general population). Looking only at the subset of patients in SUSTAIN 6 with a history of retinopathy, the Kaplan-Meier curves for new retinopathy events diverge sharply between the semaglutide-treated patients and placebo throughout the trial. On the other hand, the Kaplan-Meier curves are virtually superimposable for patients without a history of retinopathy (and the risk was much, much lower overall), suggesting that the signal is driven almost entirely by those with a history of retinopathy. In addition, as those who experienced new events had a higher mean baseline A1c, the early A1c reduction was generally larger and more dramatic than in the overall population – several commentators have suggested that a precipitous drop in A1c may be driving the retinopathy risk (something similar was seen in DCCT). Indeed, Dr. Vilsbøll showed that larger A1c reductions at week 16 were associated with higher incidence of retinopathy complications in those with baseline retinopathy, regardless of treatment with semaglutide or placebo.

• Overall, Dr. Vilsbøll characterized the retinopathy risk as manageable with appropriate patient selection. In Q&A, she was directly asked if she anticipated a black box warning or other strong language for the retinopathy risk on the semaglutide label, with the questioner drawing a comparison to the warning for pancreatitis for GLP-1 agonists. While Dr. Vilsbøll emphasized that the labeling decisions are up to the FDA, she was reassuring and expressed confidence in using semaglutide herself as a clinician. She recalled that, at the height of the pancreatitis controversy, there was not a clear understanding of the mechanism driving the potential increased risk. On the other hand, Dr. Vilsbøll feels comfortable with the current understanding and explanation of the increased retinopathy risk with semaglutide and expressed confidence that she will be able to identify which patients she should be more cautious prescribing semaglutide to. We’re reassured by Dr. Vilsbøll’s perspective, though it’s clear that significant provider and patient education on retinopathy will be required to optimize use of semaglutide in the diabetes patient population once it’s available. We hope Novo Nordisk will continue to demonstrate leadership in this area – and perhaps a positive consequence of this worrisome signal could be increased attention to retinopathy, a sometimes underappreciated complication of diabetes.
• Dr. Vilsbøll also shared further analysis of the impressive weight loss benefit associated with semaglutide, demonstrating that the weight loss cannot be attributed to GI side effects alone. Overall, patients taking semaglutide 0.5 mg experienced a placebo-adjusted weight loss of 2.87 kg (6.3 lbs) and those taking semaglutide 1.0 mg experienced a placebo-adjusted weight loss of 4.35 kg (9.6 lbs). Among participants in the semaglutide 0.5 mg arm, those who experienced nausea and vomiting experienced a placebo-adjusted mean weight loss of 2.7 kg (6.0 lbs), compared to 2.8 kg (6.2 lbs) for those who did not experience any nausea or vomiting. Similarly, among participants in the semaglutide 1.0 mg arm, those who experienced nausea and vomiting lost 4.6 kg (10.1 lbs, placebo-adjusted), compared to 4.2 kg (9.3 lbs, placebo-adjusted) among those who did not experience nausea or vomiting.

Symposium: New Learnings from the Results of the Liraglutide Effect and Action in Diabetes – Evaluation of Cardiovascular Outcome (LEADER) Trial

New Learnings – Cardiovascular Outcomes

Richard Pratley, MD (Florida Hospital, Orlando, FL)

Dr. Richard Pratley shared new cardiovascular analyses from the LEADER cardiovascular outcomes trial (CVOT) for Novo Nordisk’s GLP-1 agonist Victoza (liraglutide). Initially presented to great fanfare at ADA 2016, LEADER (n=9,340) demonstrated a 13% risk reduction for the primary 3-point MACE endpoint (non-fatal MI, non-fatal stroke, and CV death) with liraglutide therapy compared to placebo (p=0.01 for superiority). Dr. Pratley delved into several additional analyses of the cardiovascular findings, underscoring the robust nature of the benefit. Notably, the primary endpoint included only time to first occurrence of a CV event – so a person who experienced two non-fatal MIs would only count as one “event” in the primary analysis. When recurrent CV events were included in the analysis (or, in other words, when looking at the total number of non-fatal MIs, non-fatal stroke, and CV deaths that occurred in the trial), the hazard ratio remained remarkably consistent in favor of liraglutide and highly statistically significant (HR=0.86, 95% CI: 0.78-0.95, p=0.004). As Dr. Pratley put it, this finding provides a better sense of the benefit of liraglutide on the overall burden of disease since, unfortunately, recurrent CV events do occur in far too many patients (and, indeed, those with a prior CV event are at higher risk for future events). All in all, this finding provides evidence of a CV benefit of liraglutide in even the highest risk populations.

• Dr. Pratley examined the potential impact of concomitant medications on the primary outcome findings in LEADER. This is especially important as some have suggested that the LEADER findings may be driven by differences in CV medication or glucose-lowering therapy between the two arms. The investigators evaluated the impact of liraglutide on primary outcome event rate when adjusted for beta-blockers, ACE inhibitors, statins, or platelet aggregation inhibitors and the hazard ratios and 95% confidence intervals remained remarkably consistent despite these adjustments (see table below). Further, some have suggested that increased insulin, SU, or TZD usage in the placebo group during the trial could be driving the results by causing harm in the placebo arm. This hypothesis was not substantiated by the analyses presented by Dr. Pratley – the hazard ratio of benefit in favor of liraglutide also remained remarkably consistent regardless of concomitant antihyperglycemic therapy (ranging from 0.79 to 0.88, see table below for full results). This finding is particularly reassuring and further reinforces that the CV benefit of liraglutide is likely “real.” The LEADER team also examined the primary outcome results in patients who did and did not experience a severe hypoglycemia event and again found very consistent hazard ratios. We note that the confidence interval for the subgroup of those who did experience severe hypoglycemia was very, very large, likely a reflection of the relatively small number of patients who experienced this event, due in part to the impressive 31% hypoglycemia risk reduction associated with liraglutide.
• Dr. Pratley noted that the CV benefit of liraglutide is not readily explained by differences in clinical and metabolic endpoints, despite the end-of-trial differences in A1c (0.4% favoring liraglutide, p<0.001), weight (2.4 kg [5.1 lbs] favoring liraglutide, p<0.001), systolic blood pressure (1.2 mmHg favoring liraglutide, p<0.001), and lipids. Looking to A1c specifically, the rate of primary endpoint occurrence was similar across subgroups when participants were stratified by in-trial A1c reduction from baseline at six months. The primary endpoint was experienced by 15% of liraglutide-treated patients with >1.5% A1c reduction (12% of placebo patients), 13% of patients with A1c reduction between 0.4% and 1.4% (12% of placebo patients), and 14% of patients with A1c reduction <0.4% (14% of placebo patients). The similarity in event rate across the three A1c reduction subgroups suggests that it’s unlikely A1c alone that’s driving the benefit, according to Dr. Pratley.
• Overall, the additional analyses provided more information on what is not driving the CV benefit of LEADER than offering potential explanations. Given that the benefit does not appear to be driven by concomitant therapies or known metabolic characteristics of liraglutide, Dr. Pratley posited that the benefit is likely driven by “off-target” effects of GLP-1 agonism, whether acting directly on the heart or acting on the vasculature. That said, we’ve also seen some heterogeneity in the GLP-1 agonist class thus far – Novo Nordisk’s semaglutide also reported positive results in SUSTAIN 6, but Sanofi’s Lyxumia (lixisenatide), AZ’s Bydureon (exenatide once-weekly), and Intarcia’s ITCA 650 (implantable exenatide mini-pump) did not demonstrate CV superiority in their own CVOTs (though the last one was admittedly a much smaller trial designed for an easier safety threshold). Given that human GLP-1-based liraglutide and semaglutide differ substantially from the exendin-4-based GLP-1 agonists that have shared CV results thus far (and, some suggest Novo Nordisk’s compounds also differ substantially other human-based GLP-1 agonists in terms size, etc.), it’s quite possible that we’ll continue to see substantial heterogeneity in this class in our view.

Additional CV Analyses for LEADER

Analysis	Primary outcome hazard ratio (95% CI)
Unadjusted primary finding	0.87 (0.78-0.97)
Recurrent CV events included	0.86 (0.78-0.95)
Adjusted for beta-blockers at baseline	0.86 (0.77-0.96)
Adjusted for ACE inhibitors at baseline	0.87 (0.78-0.97)
Adjusted for statins	0.87 (0.78-0.97)
Adjusted for platelet aggregation inhibitors	0.87 (0.78-0.97)
Subgroup of those on insulin at baseline	0.88 (0.75-1.03)
Subgroup of those not on insulin at baseline	0.86 (0.74-1.01)
Subgroup of those never treated w/ insulin during trial	0.82 (0.68-0.98)
Subgroup of those never treated w/ SU during trial	0.79 (0.67-0.94)
Subgroup of those never treated w/ TZD during trial	0.87 (0.78-097)
Subgroup of those who did not experience severe hypoglycemia during trial	0.88 (0.78-0.98)
Subgroup of those who did experience severe hypoglycemia during trial	0.85 (0.52-1.39)

New Learnings – Secondary Outcomes

Stephen Bain, MD (Swansea University, Swansea, UK)

Dr. Bain offered additional granularity on the impressive secondary microvascular benefit observed in the LEADER trial. At ADA 2016, the LEADER investigators shared that liraglutide therapy produced a 16% statistically significant improvement in time to first microvascular event (encompassing renal and ophthalmic adverse outcomes; 95% CI: 0.73-0.97, p=0.02), driven entirely by a 22% statistically significant improvement in renal outcomes (95% CI: 0.67-0.92, p=0.003). There was no statistically significant improvement in eye outcomes – the hazard ratio was 1.15 (95% CI: 0.87-1.52, p=0.33). Focusing on the renal outcome, Dr. Bain showed that the results remained virtually the same when adjusted for use of RAAS inhibitors at baseline (HR=0.78, 95% CI: 0.67-0.92, p=0.002). Expanding upon the urinary albumin-to-creatinine ratio (UACR) data presented at EASD 2016 (in which liraglutide produced a 19% reduction in urinary albumin-creatinine ratio, a measure of microalbuminuria [HR=0.81, 95% CI: 0.76-0.86]), Dr. Bain showed that the estimated treatment ratio was comparable regardless of whether patients’ had normal albuminuria (HR=0.86; 95%CI: 0.80-0.93), microalbuminuria (HR=0.76; 95% CI: 0.67-0.85), or macroalbuminuria (HR=0.87; 95% CI:0.72-1.06).

• Dr. Bain also offered an exciting expanded look at the glycemic and patient-reported outcomes associated with liraglutide therapy in LEADER. Participants in the liraglutide arm of the trial were 79% more likely to achieve an A1c<8% and more than twice as likely to achieve an A1c <7.5% or <7% compared to placebo at three years. Even more impressively, liraglutide therapy was associated with a significant delay in time to insulin initiation, producing a 48% relative risk reduction in insulin initiation (HR=0.52, 95% CI: 0.48-0.58). The results were similar for time to initiation of insulin or of any new oral agent: liraglutide was associated with a 37% risk reduction for therapy intensification (HR=0.63; 95% CI: 0.59-0.68). We’ve long felt that earlier use of GLP-1 agonists could delay the need for treatment intensification (and the associated hypoglycemia, weight gain, etc. concerns associated with insulin) and we’re pleased to see long-term clinical evidence in support of this. We were also extremely pleased to see patient-reported quality of life results from one of the largest trials of a GLP-1 agonist to date. In LEADER, liraglutide demonstrated superiority in both the European Quality of Life (EQ-5D) index score (p=0.020) and the EQ-5D visual analog scale (VAS) score (p=0.019).

Oral Presentations: New Insights into Prevention and Treatment of Hypoglycemia

Severe Hypoglycemia, Cardiovascular Outcomes, and Death – The LEADER Experience

Bernard Zinman, MD (University of Toronto, Canada)

Presenting additional data from LEADER, Dr. Bernard Zinman ruled out hypoglycemia as a mediating factor between liraglutide and reduced risk for three-point MACE (non-fatal MI, non-fatal stroke, and CV death) but emphasized that hypoglycemia is an independent CV risk factor. Separating participants into two subgroups, Dr. Zinman reported a 15% relative risk reduction for three-point MACE among patients who experienced severe hypoglycemia during the course of the trial (HR=0.85; 95% CI: 0.52-1.39) and a 12% relative risk reduction for three-point MACE among those who did not (HR=0.88; 95% CI: 0.78-0.98). The p-value for this interaction was a nonsignificant 0.9, meaning that severe hypoglycemia did not interfere with liraglutide’s CV effects. This echoed a major theme of an ADA day #3 symposium on post-hoc LEADER analyses – new post-hoc analyses suggest that third-party variables like hypoglycemia are not likely confounders, supporting the conclusion that something about the liraglutide molecule itself confers cardioprotection. That said, an episode of severe hypoglycemia in LEADER substantially increased risk for a MACE event in the seven days following, by a remarkable 6x (HR=7.3, 95% CI: 1.8-29, p<0.05). This risk was still significantly raised vs. study participants who didn’t experience severe hypoglycemia in the 15 days following an event, 30 days, 60 days, 90 days, 180 days, and 365 days, though by a smaller margin as more time passed. Dr. Zinman shared data on this heightened risk for MACE events in the aftermath of severe hypoglycemia across both the liraglutide and placebo arms after adjusting for sex, age, concomitant medications (including insulin), baseline A1c, and diabetes duration. He showed significantly heightened risk for CV death and non-CV death following severe hypoglycemia as well. In all cases, there’s a curve for the correlation between a severe hypoglycemic event and CV risk, with the greatest relative risk increase in the week immediately following. Dr. Zinman explained the wide confidence intervals in terms of a low number of events, but given the critical importance of hypoglycemia in diabetes and CV disease, he advocated for further research on this front. As he put it, minimizing hypoglycemia remains an essential goal in optimal management of diabetes, which now more than ever includes delaying/preventing CV events – notably, all the diabetes drugs that have demonstrated a cardioprotective benefit thus far also carry a low risk of hypoglycemia and we continue to believe that much access work needs to be done to ensure patients are able to benefit from these incredible agents. We’d love to see analysis of the opposite relationship as well – whether a history of CV events raises risk for severe hypoglycemia. We previously saw an intriguing and worrisome analysis to this effect from the TECOS dataset at ESC 2016 and we’d love to see further evidence from other trials (given that, beyond the primary endpoint findings, CVOTs offer an incredible opportunity and large datasets to inform other aspects of clinical practice).

Oral Presentations: Landscape of Therapeutic Trials in Type 2 Diabetes

Efficacy and Safety of Insulin Degludec/Liraglutide (IDegLira) vs. Basal-Bolus (BB) Therapy in Patients with Type 2 Diabetes (T2D): DUAL VII Trial

Liana Billings, MD (North Shore University Health System, Skokie, IL)

To numerous rounds of thunderous applause, Dr. Liana Billings (North Shore University Health System, Skokie, IL) presented the impressive results of the DUAL VII trial comparing the safety and efficacy of Novo Nordisk’s Xultophy (insulin degludec/liraglutide) versus traditional basal-bolus therapy in type 2 diabetes. People with type 2 diabetes on insulin glargine (n=506) were randomized in an open-label setting to once-daily Xultophy for 26 weeks or to basal-bolus regimen with insulin glargine and insulin aspart. The trial met its primary endpoint by demonstrating that treatment with Xultophy is non-inferior to basal-bolus therapy with respect to A1c lowering (-1.48% vs. -1.46%, baseline A1c 8.2%) and furthermore demonstrated superiority for a host of secondary outcomes. Compared to basal-bolus therapy, average total daily insulin dose among those taking Xultophy was less than half that of those on basal-bolus therapy (40 vs. 84 units; p<0.001). The end-of-trial body weight difference was also substantially in favor Xultophy (-0.93 kg [2.1 lbs] vs. +2.64 kg [5.8 lbs], p<0.001). Very notably, Xultophy additionally proved superior in terms of hypoglycemia: only 20% of participants in the Xultophy arm experienced blood glucose-confirmed symptomatic or severe hypoglycemia during the study period, versus a whopping 53% of participants in the basal-bolus therapy arm, an extremely impressive 89% risk reduction (HR= 0.11; 95% CI: 0.08-0.17; p<0.0001). Xultophy’s safety profile remained consistent with previous findings; unsurprisingly, nausea was the most frequently-reported adverse event (28 patients in the treatment arm vs. 4 in the basal-bolus arm), but Dr. Billings pointed out that only <3% of the participants in the IDegLira arm experienced nausea at any given time. Indeed, as we understand it, the basal insulin component of these combinations can mitigate the GI side effects typically associated with GLP-1 agonists. During Q&A, the esteemed Dr. Julio Rosenstock deemed this the "most robust, most impressive piece of data I've seen in years." We are equally impressed with these clinical advantages for Xultophy over traditional basal-bolus treatment regimen – especially in terms of the crucial outcome of hypoglycemia risk reduction – and hope these findings help to advance the uptake of the emerging class of GLP-1 agonist/basal insulin co-formulations. We expect to continue to see increasing preference for GLP-1 agonists over prandial insulin as a basal intensification option, and DUAL VII lends strong clinical evidence for this choice. We’ll be back with more on DUAL VII with our take on additional analyses, presented in two posters: one on the cost effectiveness of Xultophy (981-P) and another detailing patient-reported outcomes from DUAL VII (124-LB). While we are happy to see this research, it is our sense that it is extremely challenging for patients to actually gain access to this therapy, despite now years of robust praise.

Oral Presentations: GLP-1s and SGLT2s—To Do or Not to Do in Type 1 Diabetes Mellitus?

Efficacy and Safety of Liraglutide in Insulin-Pump-Treated People with Type 1 Diabetes: The Lira Pump Trial

Thomas Dejgaard, MD; Kirsten Nørgaard, MD; Christian Frandsen, MD (Copenhagen University Hospital, Hvidovre, Denmark)

A team of researchers from Copenhagen University Hospital (Hvidovre, Denmark) presented the results of the highly-anticipated Lira Pump Trial demonstrating the clinical potential of the GLP-1 agonist liraglutide as an addition to insulin pump treatment in people with type 1 diabetes. People with type 1 diabetes using CSII and with overweight (n=44) were randomized to receive liraglutide 1.8 mg or placebo in addition to regular insulin pump therapy for 26 weeks. Dr. Thomas Dejgaard outlined the positive primary outcomes: compared to placebo, liraglutide as an add-on to insulin pump treatment produced significant improvements in A1c (-0.6% vs. +0.2%; p<0.001) and weight loss (-7.3 kg [16.1 lbs] vs. -0.6 kg [1.3 lbs]; p<0.001) without increasing the time spent in hypoglycemia (3.2 vs. 3.5 events; p=0.77). While the A1c reduction could be characterized as modest for a GLP-1 agonist, we’re especially impressed by the reduction from a presumably low baseline A1c combined with the substantial weight loss. As expected for a GLP-1 agonist, nausea was the most commonly reported adverse event for participants randomized to the liraglutide treatment arm; 64% of participants experienced this, though it was transient and disappeared over the first few weeks of the study (we’d love to better understand the experience and intensity of nausea since this percentage isn’t that helpful overall). Currently approved for type 2 diabetes (under the trade name Victoza) and obesity (under the trade name Saxenda), these results underscore the potential of liraglutide for type 1 diabetes as well.

• Dr. Kirsten Nørgaard followed with a deeper dive into the impact of add-on liraglutide to insulin dosing and time-in-range. Excitingly, liraglutide as an add-on to insulin pump therapy gave participants significantly more time spent in the normoglycemic range (57% vs. 45%) – a crucial outcome for patient quality of life and perceived therapeutic and personal success. That said, there was no statistically significant difference in time spent in hypoglycemia (defined as <3.9 mmol/l [70 mg/dl]). Very surprisingly (shockingly), liraglutide also produced no change in total daily dose of insulin; it is less surprising that the distribution between basal and bolus insulin also wasn’t changed.
• Dr. Christian Frandsen closed with a closer look at the effect of liraglutide on weight loss. In addition to producing significant reductions in the primary outcome of body weight, liraglutide also produced reductions in a number of more specific measures of body composition, including total fat, android fat, gynoid fat, and total lean mass. The mechanism of this effect is unclear but likely is not related to food preferences. As revealed by food preference surveys given throughout the study, liraglutide did not appreciably impact food preferences.

Questions and Answers

Q: Your group has already presented nice studies in obese and non-obese people with type 1 diabetes on MDI. What is different about this CSII population that the outcomes are so much better?

A: The A1c reduction in liraglutide treated patients were exactly the same (0.6%) between these trials. The major difference is that here we didn’t see an appreciable A1c change in the patients in the placebo arm, whereas we saw a -0.4% A1c reduction in the placebo arm in the other studies, leaving no significant difference between the treatment and control groups.

Q: Why the choice of a 1.8 mg dose of liraglutide? You showed very impressive weight loss – is this because people with type 1 are more sensitive to the drug? Did any participants need a reduction in dose?

A: I don’t think it’s true that people with type 1 diabetes are more sensitive to liraglutide. A few patients had to reduce to a 1.2 mg dose to minimize nausea side effects.

Q: Do you think these improvements you’re seeing are due to weight loss?

A: A large part of it could be the weight loss, that’s possible.

Oral Presentations: Landscape of Therapeutic Trails in Type 2 Diabetes

Efficacy and Safety of Exenatide QW vs. Placebo Added to Insulin Glargine in Uncontrolled Basal-Insulin Treated Type 2 Diabetes: DURATION-7 Trial

Juan Frias, MD (National Research Institute, Los Angeles, CA)

In a packed oral session, Dr. Juan Frias (National Research Institute, Los Angeles, CA) presented the results from the DURATION-7 study, demonstrating clinical glycemic and weight benefits for AZ’s GLP-1 agonist Bydureon (exenatide once-weekly) as an add-on to insulin therapy in people with type 2 diabetes. Participants already on insulin therapy (n=461) were randomized to once-weekly Bydureon or placebo in combination with their existing insulin regimen. With Bydureon, participants experienced a significantly greater mean reduction in A1c (-1.0% vs. -0.3%, baseline A1c=8.5%, p<0.01) after 28 weeks, and 25% more patients in the Bydureon treatment arm achieved an A1c of <7% by the end of the study. Therapeutic intensification with Bydureon furthermore reduced fasting plasma glucose and 2-hour postprandial glucose by an average of 9 mg/dl (p=0.028) and 27 mg/dl (p<0.001) versus placebo, respectively. Notably, participants in the Bydureon arm additionally lost an average of 1.5 kg (3.3 lbs) relative to placebo (p<0.001), and 20% more participants using Bydureon achieved the composite endpoint of an A1c <7% with no weight gain or major hypoglycemia. Participants taking add-on Bydureon also experienced a 2 unit/day decrease in daily insulin requirements, but this did not achieve statistical significance (p=0.07). Adverse events were not significantly different between the treatment and placebo arms (125 vs. 133 events); gastrointestinal complaints were numerically higher in the exenatide group (35 vs. 25 events), as expected with a GLP-1 agonist, and no severe hypoglycemia events occurred in either treatment arm. Together these results underscore the superiority of exenatide once-weekly in combination with basal insulin over basal insulin therapy alone.

Oral Presentations: Beyond Glycemic Impact

Semaglutide Provides Superior Body Weight Reduction across SUSTAIN 1-5 Clinical Trials

Ildiko Lingvay, MD (University of Texas Southwestern Medical Center, Dallas, TX)

Dr. Ildiko Lingvay (University of Texas Southwestern Medical Center, Dallas, TX) presented a meta-analysis of the phase 3 SUSTAIN 1-5 clinical trials, demonstrating that Novo Nordisk’s once-weekly GLP-1 agonist semaglutide provided clinically meaningful and superior reductions in body weight across all five studies, versus a range of tested comparator drugs and in a broad range of patient populations. As a reminder, SUSTAIN 1 tested semaglutide against placebo (n=388; 30 weeks) in treatment-naïve patients, SUSTAIN 2-4 tested semaglutide head-to-head against other diabetes drugs in patients on metformin (sitagliptin in SUSTAIN 2 [n=1,231; 56 weeks], exenatide once-weekly in SUSTAIN 3 [n=813; 56 weeks], and insulin glargine in SUSTAIN 4 [n=1,089; 30 weeks]), and SUSTAIN 5 tested semaglutide against placebo as an add-on therapy in patients on metformin and insulin (n=397; 30 weeks). Average A1c and BMI at baseline were similar across all five studies, ranging from 8.1-8.4% and 32-34 kg/m². Impressively, Dr. Lingvay outlined that significantly greater absolute reductions in body weight were seen with semaglutide across the entire SUSTAIN program. Participants on 1.0 mg semaglutide lost an average of 4.5 kg (9.9 lbs) in SUSTAIN 1 (versus -1 kg [2.2 lbs] with placebo), -6.1 kg (13 lbs) in SUSTAIN 2 (versus -1.9 kg [4.2 lbs] with sitagliptin), -5.6 kg (12 lbs) in SUSTAIN 3 (versus -1.9 kg [4.2 lbs] with exenatide once-weekly), -5.2 kg (11.5 lbs) in SUSTAIN 4 (versus +1.2 kg [2.6 lbs] with insulin glargine), and -6.4 kg [14 lbs] in SUSTAIN 5 (versus -1.4 kg [3.1 lbs] with placebo). Across the entire SUSTAIN program, participants on 1.0 mg semaglutide also achieved >10% weight loss significantly more often than those in the comparator group. The proportion of patients achieving this weight loss goal reached 13% in SUSTAIN 1 (versus 2% with placebo), 24% in SUSTAIN 2 (versus 3% with sitagliptin), 21% in SUSTAIN 3 (versus 4% with exenatide once-weekly), 16% in SUSTAIN 4 (versus 2% with insulin glargine), and 26% in SUSTAIN 5 (versus 3% with placebo). Dr. Lingvay alluded that longer-term data from the SUSTAIN 6 trial demonstrates that semaglutide’s impressive weight loss effects can be sustained for at least 2 years (more on this coming soon in our coverage of poster 1125-P) and that these weight loss effects are accompanied by significant reductions in A1c as well (results are detailed in poster 1124-P) Given that ~90% of people with type 2 diabetes struggle with overweight or obesity, weight management is a crucial advantage in a potential new diabetes medication, and all this is in addition to semaglutide’s added ability to reduce the risk of cardiovascular death, as demonstrated in the SUSTAIN 6 CVOT. Given this extremely promising clinical profile, this candidate, we expect the product is poised to perform very well in the booming GLP-1 agonist market. An FDA decision and an EU CHMP opinion for the submissions of once-weekly, injectable semaglutide for type 2 diabetes are expected in 4Q17 according to Novo Nordisk’s last earnings update. A more patient-friendly oral version of semaglutide remains in phase 3 development.

Double-Blind, Placebo-Controlled, Randomised Trial to Assess the Effect of Liraglutide on Left Ventricular Diastolic Dysfunction in Type 2 Diabetes Mellitus Patients

Maurice Bizino, MD (Leiden University Medical Center, Leiden, Netherlands)

Dr. Maruice Bizino presented results from a small trial (n=50) demonstrating no improvement in left ventricular diastolic dysfunction (LVDD) with Novo Nordisk’s Victoza (liraglutide) vs. placebo and some potentially detrimental effects on diastolic filling. The study was initiated based on the hypothesis that Victoza could have a beneficial effect on LVDD because it promotes weight loss and preclinical studies have shown evidence that it can reverse cardiac defects. The trial enrolled 50 patients with type 2 diabetes and asymptomatic LVDD who were randomized to receive either Victoza or placebo for six months in addition to standard of care. At the end of the study period, Victoza produced essentially the expected effects on metabolic parameters: weight loss, increased heart rate, and comparable changes in blood pressure and A1c. The results on heart failure parameters were more surprising and disappointing. Victoza did not improve LVDD and in fact reduced early diastolic filling and left ventricular filling pressure. Dr. Bizino explained that a reduction in preload (the tension in cardiac muscle right before contraction, approximated by end diastolic volume) was the most likely explanation for the change in filling pattern. He stressed that the overall conclusions of these results are not obvious – lowering filling pressure could be helpful in some cases, but it could also be detrimental specifically in patients with heart failure and preserved ejection fraction (HFpEF). He concluded his talk by calling for the inclusion of more patients with subclinical cardiovascular disease in CVOTs for diabetes drugs and for additional safety trials of Victoza in patients with HFpEF (likely a long shot given the results from the LEADER trial showing that Victoza had no effect on hospitalization for heart failure and the FIGHT trial found no benefit for Victoza in patients hospitalized for acute heart failure).

Questions and Answers

Q: Based on this, I would think a large trial like LEADER would have shown increased hospitalization for heart failure but it obviously didn’t. Does that give you confidence or do we need further studies?

A: I’m aware of the big trials and the effect of liraglutide on heart failure but I do think those are different patients. In this small study we see a dramatic effect. That’s a reason for further investigation. In addition, patients with diastolic dysfunction are not as recognized as those with systolic heart failure. Those are two reasons why further investigations are needed.

Q: Do you have data on systolic function and left atrial and left ventricular size and volume? There also should have been a change in end diastolic volume if it’s preload.

A: We looked at systolic function and heart images. Systolic function was slightly decreased; stroke volume and ejection fraction were decreased by 2%. End diastolic volume was also significantly decreased. Left atrial volume went in the same direction but there was not a significant difference.

Q: There was significant weight loss in the study. Was there any association between weight loss or other factors and changes in diastolic function?

A: No. We tried to correlate gender and insulin use and there was no correlation whatsoever.

Oral Presentations: Obesity Pathogenesis and Treatment – Insights from Mouse Models

PB-718, a Dual GLP-1/Glucagon Receptor Agonist Demonstrates Superior Weight Loss Effect and Ameliorates Nonalcoholic Steatohepatitis (NASH) in Animal Models

Michael Xu, MD (Pegbio, Suzhou, China)

Dr. Michael Xu presented a range of preclinical data on an investigational, PEGylated GLP-1/glucagon receptor dual agonist – Pegbio’s PB-718. In a mouse model of diabetes (n=6), both low and high doses of the agent were associated with superior weight loss and reduced fasting plasma glucose vs. twice-daily liraglutide. In mice with NASH (n=6), both doses led to more weight loss, a greater reduction in liver weight, and a greater lowering of liver weight/body weight ratio vs. placebo (p<0.0001 for all comparisons). Moreover, there was a dose-dependent reduction in NAS score for NASH severity (p<0.01 for lower dose vs. placebo; p<0.0001 for higher dose vs. placebo), which takes into account steatosis, liver inflammation, fibrosis, and other markers. Dr. Xu also reviewed findings from a preclinical investigation of Pegbio’s drug candidate in monkeys. Consistent with the data from rodent studies, PB-718 demonstrated dose-dependent and significant superiority vs. placebo in stimulating weight loss and improving NAS score. Dr. Xu explained that there are strong mechanistic underpinnings that support the utility of GLP-1/glucagon dual agonists for diabetes, obesity, and NASH. Oxynotomodulin, an endogenous dual agonist of GLP-1/glucagon, has been correlated with decreased food intake, enhanced glucose tolerance, and improved liver health. We’re certainly excited by GLP-1/glucagon dual agonists as a potential new therapy class (competitive landscape here), and we’re happy to see companies investing in these agents for diabetes as well as adjacent indications. NASH, in particular, is a therapeutic area of high unmet need with no FDA-approved medicines to-date, and we also see marked room for improvement in available tools for obesity management.

Questions and Answers

Q: Have you compared your agent with semaglutide (Novo Nordisk’s GLP-1 agonist candidate, in phase 2 for obesity and NASH)?

A: No we have not, but we will be eager to compare our compound to semaglutide in some study. Actually, we were approached by them and tried to figure out how to compare these compounds side-by-side. Of course, semaglutide has not yet been approved.

Oral Presentations: Translating Therapeutics into the Real World

Value Index Favors Using GLP-1 More Than DPP-4, Saving Medicare $200 Million

Saad Sakkal, MD (Metabolic Care Center, Mason, OH)

Dr. Saad Sakkal defined the value index in diabetes as the amount of money spent to improve A1c by 1% in three months. According to Medicare pricing, the value index for DPP-4 inhibitors was calculated at $927 vs. $750 for GLP-1 agonists. If Medicare switched the 1,197,066 patients currently on a DPP-4 inhibitor onto a GLP-1 agonist, it could save up to $211,880,682 annually. For context, the annual cost of diabetes care nationally is around $340 billion, and this is expected to rise. This analysis reflects the clinical trial data showing that GLP-1 agonists are more effective than DPP-4 inhibitors, and we now have cost-savings information to support greater use and better reimbursement prospects for products in the GLP-1 class. In light of this information, we’d also love to see future studies comparing the value index between other therapy classes beyond GLP-1 agonists and DPP-4 inhibitors. 

Posters

DURATION-8 Randomized Controlled Trial 1-Year Results: Efficacy and Safety of Once-Weekly Exenatide (ExQW) Plus Once-Daily Dapagliflozin (DAPA) vs. ExQW or DAPA Alone (141-LB)

C Guja, J Frias, A Ahmed, E Hardy, H Wang, P Ohman, and S Jabbour

AZ presented new one-year DURATION-8 results, demonstrating that the combination of AZ’s SGLT-2 inhibitor Farxiga (dapagliflozin) and once-weekly GLP-1 agonist Bydureon (exenatide) maintained improvements in glycemic control, body weight, and SBP compared to either drug alone. These results represent the 24-week extension from the promising 28-week DURATION-8 results presented at this past EASD meeting. In this double-blind, multicenter study, adults with type 2 diabetes were randomized to either exenatide plus dapagliflozin, exenatide alone, or dapagliflozin alone. Of the initial 695 patients randomized, 564 (81%) completed the full 52-week treatment period. The findings demonstrated that at week 52, the combination therapy group continued to achieve greater reductions in A1c, FPG, 2-hour PPG, body weight, and SBP compared to either treatment group alone. Specifically, the -1.8% A1c reduction for exenatide/dapagliflozin dual therapy significantly exceeded those of exenatide (-1.4%; p<0.01) and dapagliflozin (-1.2%; p<0.01) alone. Notably, Body weight reductions were -3.3 kg for the dual therapy arm, significantly greater than -1.5 kg for exenatide monotherapy (p<0.001) and -2.3 kg for dapagliflozin monotherapy (p<0.001). SBP reductions were 4.5 mmHg, 0.7 mmHg (p<0.001), and 2.7 mmHg, respectively. Regarding safety and tolerability, the combination therapy was well tolerated, with slightly more adverse events vs. either drug alone (66.2% vs. 62.2% [exenatide] and 61.8% [dapagliflozin]), though the three groups had comparable rates of serious adverse events. In general, patients treated with exenatide unsurprisingly reported more GI adverse events. These results confirm the promising findings that made waves at last EASD and the excitement surrounding the GLP-1/SGLT-2 combination approach. As both of these classes have the potential for CV risk reduction, we would be interested to see if a combination therapy could provide further additive benefits. For more on DURATION-8 and AZ’s latest, please see our EASD 2016 and 1Q17 coverage.

Patient-Reported Outcomes (PROs) in Insulin Degludec/Liraglutide (IDegLira) vs. Basal-Bolus (BB) Therapy in Patients (Pts) with Type 2 Diabetes (T2D): DUAL VII Trial (124-LB)

LK Billings, A Doshi, D Gouet, A Oviedo, HW Rodbard, N Tentolouris, AK Busk, A Basse, and E Jodar

This poster overviewed patient-reported outcomes (PROs) from the DUAL VII trial, demonstrating that treatment with Novo Nordisk’s Xultophy (insulin degludec/liraglutide) resulted in greater improvements related to diabetes management, treatment burden, and adherence than treatment with basal-bolus therapy. People with type 2 diabetes on insulin glargine (n=506) were randomized in an open-label setting to once-daily Xultophy for 26 weeks or to basal-bolus regimen with insulin glargine and insulin aspart. In assessing PROs, the Treatment-Related Impact Measure for Diabetes (TRIM-D) questionnaire, which consists of 28 questions across five domains, showed significant moderate significant improvements for patients on Xultophy versus basal bolus therapy in all domains, including diabetes management, treatment burden, compliance, daily life, and psychological health. After 26 weeks, total score change from baseline was +9.2 for the Xultophy group, versus +3.5 for basal bolus therapy (p<0.0001). Furthermore, the Short Form-36 version 2 questionnaire (SF-36), which consists of 36 items across eight domains, showed small improvements in all domains with Xultophy, with a significant benefit for Xultophy over basal bolus therapy in the mental health component of the survey (+2.5 vs. -0.2, p=0.0074). Additionally, after 26 treatment weeks, 85% of participants in the Xultophy arm were “very” or “extremely” willing to continue their treatment, versus only 68% of participants in the basal-bolus therapy arm. These results demonstrate that in addition to the glycemic and weight loss benefits for Xultophy demonstrated in the main DUAL VII results, this drug may have additional benefits for perception of outcomes by the patient – a major win in our eyes in terms of outcomes beyond A1c. We imagine that this improved perception of treatment outcomes with Xultophy could be influenced by better glycemic control, fewer injections, weight loss, or lower rates of hypoglycemia. However, it should be noted that this was an open-label trial, and these results could be influenced as such.

Comparable Glycemic Control, Greater Weight Loss, and Lower Hypoglycemia with Once Weekly Dulaglutide Versus Insulin Glargine, Both Combined with Lispro, in Type 2 Diabetes and Moderate to Severe Chronic Kidney Disease (AWARD-7) (138-LB)

KR Tuttle, MC Lakshmanan, JL Gross, B Rayner, RS Busch, B Woodward, AG Zimmermann, and FT Botros

The 52-week AWARD-7 trial evaluated GLP-1 agonist dulaglutide (Lilly’s Trulicity) in a head-to-head comparison with insulin glargine (Sanofi’s Lantus), both in combination with insulin lispro (Lilly’s Humalog) in patients with chronic kidney disease. Primary endpoint results of A1c change at 26 weeks were reported in this poster, as were safety findings. The trial randomized 576 patients with eGFR between 15 and 60 ml/min/1.73m² to either dulaglutide 1.5 mg, dulaglutide 0.75 mg, or titrated insulin glargine. AWARD-7 met its primary endpoint by demonstrating non-inferiority to insulin glargine in terms of A1c reduction: mean A1c reduction was 1.19% in the dulaglutide 1.5 mg group, 1.12% in the dulaglutide 0.75 mg group, and 1.13% in the insulin glargine group (baseline A1c=8.6%, p<0.001 for all comparisons to baseline). This similarity in A1c occurred in the context of increases in fasting plasma glucose (FPG) in the dulaglutide groups (+23.1 mg/dl in the dulaglutide 1.5 mg group and +17.7 mg/dl in the dulaglutide 0.75 mg group), compared to a reduction in FPG in the insulin glargine group (-19.1 mg/dl; p<0.001 compared to both dulaglutide arms). This suggests that dulaglutide has a greater effect on postprandial glucose lowering, as is expected for a GLP-1 agonist.  Similar proportions of participants achieved A1c<8% and A1c<7% in each group.

• Very notably, dulaglutide was associated with substantial weight loss and hypoglycemia benefits compared to insulin glargine. The 0.75 mg and 1.5 mg doses of dulaglutide produced mean body weight reductions of ~2 kg (~4.4 lbs) and ~3 kg (~6.6 lbs), respectively, compared to a weight increase of ~1 kg (2.2 lbs) in the insulin glargine group. Compared to insulin glargine, dulaglutide was also associated with a significantly lower rate of total hypoglycemia (p<0.001), documented symptomatic hypoglycemia (p<0.001), and nocturnal hypoglycemia (p<0.001). In addition, the higher 1.5 mg dose was associated with a lower rate of severe hypoglycemia as well (p<0.05). Participants did not wear CGM during this study, so it’s possible that these results underestimate the rate of documented symptomatic and nocturnal hypoglycemia – we would love to see greater use of CGM in these types of studies to better characterize potential hypoglycemia benefits. Notably, these improvements in hypoglycemia occurred in the context of slightly greater increases in insulin lispro dose in the dulaglutide group compared to the insulin glargine group. From a baseline insulin lispro dose of about 0.25 U/kg, lispro dose increased to ~0.4 U/kg in the glargine group, while lispro dose increased to ~0.45 U/kg in the dulaglutide 1.5 mg group and to ~0.5 U/kg in the dulaglutide 0.75 mg group.
• Adverse events were as expected, with a higher rate of nausea, vomiting, and diarrhea in the dulaglutide-treated group. All other adverse event rates were comparable between the two groups.
• Even more intriguingly, secondary endpoint data demonstrating a potential renal-protective effect of dulaglutide on eGFR compared to insulin glargine was presented in a separate late-breaking poster (142-LB). See below for our coverage.

Dulaglutide versus Glargine, Both Combined with Lispro, Mitigated eGFR Decline in People with Type 2 Diabetes and Moderate to Severe Chronic Kidney Disease (AWARD-7) (142-LB)

KR Tuttle, MC Lakshmanan, JL Gross, B Rayner, RS Busch, AG Zimmermann, A Haupt, DB Woodward, and FT Botros

This poster detailed results for a pre-specified secondary endpoint of impact on eGFR and albuminuria in the AWARD-7 trial. The AWARD-7 study team, led by Dr. Katherine Tuttle, evaluated the effect of dulaglutide (Lilly’s Trulicity) vs. insulin glargine (Sanofi’s Lantus), both in combination with insulin lispro (Lilly’s Humalog), in patients with type 2 diabetes and moderate to severe chronic kidney disease. The 52-week trial randomized 576 patients with eGFR between 15 and 60 ml/min/1.73m² to either dulaglutide 1.5 mg, dulaglutide 0.75 mg, or titrated insulin glargine. Very impressively, dulaglutide treatment appeared to mitigate further eGFR decline throughout the trial. While eGFR declined by an average of 1.9 in the insulin glargine group at 26 weeks, eGFR only declined by 0.1 and 0.4 in the 1.5 mg and 0.75 mg groups, respectively. Baseline eGFR was around 38 in all three treatment arms. The treatment difference in eGFR decline for the 1.5 mg and 0.75 mg groups was thus, respectively, 1.8 and 1.6 (p<0.05 for both comparisons to insulin glargine). By percent change from baseline, those in the insulin glargine group experienced a 7.7% decline in eGFR, while those in the dulaglutide 1.5 mg arm experienced a 0.8% decline in eGFR (p<0.05 vs. insulin glargine), and those in the dulaglutide 0.75 mg arm experienced a 3.3% decline in eGFR (p<0.05 vs. insulin glargine). Furthermore, the percent decline in eGFR in both of the dulaglutide arms was not statistically significant compared to baseline, while the decline in the insulin glargine arm was highly statistically significant (p<0.001). These differences in eGFR were driven by an apparent protective effect in patients with macroalbuminuria at baseline. On the other hand, UACR was reduced in all three treatment arms and the between-treatment difference was non-significant for this endpoint. From a safety standpoint, there were no significant differences between dulaglutide and insulin glargine for renal events of interest. Overall, these results – while only hypothesis-generating – are certainly extremely intriguing. At the very least, we can largely rest assured that dulaglutide does not increase renal risk compared to insulin glargine. Further, there appears to be a suggestion of renal benefit that we would love to see characterized further when the REWIND trial for Trulicity reports in July 2018. The LEADER and SUSTAIN 6 trials for Novo Nordisk’s GLP-1 agonists Victoza (liraglutide) and semaglutide both demonstrated a potential beneficial effect for these agents on hard renal endpoints and it would be amazing to see that corroborated in REWIND.

• Primary endpoint and safety results were presented in poster 138-LB (see above).

Real-World Use of IDegLira Significantly Improves Glycemic Control in Patients with T2D (988-P)

H Price, B Schultes, R Prager, T Phan, B Thorsted, and M Bluher

Drawing on dataset from the multi-center, retrospective EXTRA study, this poster demonstrated improvements in glycemic control, body weight, and hypoglycemia risk associated with Novo Nordisk’s Xultophy (insulin degludec/liraglutide) in a real-world setting. The EXTRA study included data (from EMRs) for 611 adult patients with type 2 diabetes in five European countries. All participant had been taking Xultophy for at least six months at time of analysis. Meeting its primary endpoint, the study found a mean A1c reduction of 0.9% six months after initiation of Xultophy (p<0.0001); similar results were observed at 3 and 12 months. A1c reductions were observed regardless of baseline therapy at time of initiation (e.g. basal insulin, oral antidiabetic drugs, GLP-1 agonists, etc.) Fasting plasma glucose also decreased by an average of 45.8 mg/dl at six months (p<0.0001). This reduction was sustained at 12 months as well (mean reduction of 44.5 mg/dl, p<0.05). Adding to these benefits, investigators also found a 0.7 kg (1.5 lbs) reduction in body weight at 6 months (p<0.05), though this varied depending on pre-study treatment regimens (weight expectedly increased with Xultophy therapy in those on just GLP-1 agonists and oral agents at baseline, for instance). The MDI at baseline subgroup was the only one that experienced significant weight loss following Xultophy initiation in this subgroup analysis – of course, subgroup analyses are notorious finicky with small sample sizes, so it’s quite likely that the weight benefits of Xultophy apply to the other subgroups as well. On the safety side of things, hypoglycemia events per patient-year decreased from 0.28 to 0.06 after Xultophy initiation — a very impressive 81% reduction (p=0.0001). Ultimately, this study shows that Xultophy is effective at improving glycemic control and reducing risk of hypoglycemia in routine clinical practice, outside of an interventional study.

Results of a Phase 2 Study of the Oxyntomodulin (OXM) Analogue LY2944876 in Patients with Type 2 Diabetes (T2DM) (1070-P)

M Sheetz, R Bray, LS Tham, C Jones, J Kinsella, and R Violante-Ortiz

Lilly presented full phase 2 results for its PEGylated GLP-1/glucagon dual agonist, oxyntomodulin analog LY2944876 in patients with type 2 diabetes. In this 24-week trial, 420 patients were randomized to once-weekly injections of one of four doses of LY2944876 (10 mg, 15 mg, 30 mg, or 50 mg), exenatide once-weekly (AZ’s GLP-1 agonist Bydureon), or placebo. At both week 12 and week 24, LY2944876 demonstrated superiority to placebo and non-inferiority to exenatide for the primary endpoint of A1c reduction. A1c reductions were largely dose-dependent for LY2944876 and ranged from ~0.8% to ~1.4%. At the highest 50 mg dose, LY2944876 produced statistically superior weight reductions compared to exenatide and placebo (p=0.044 and p=0.007, respectively). However, the finding did not achieve the predefined criterion for superior weight loss (a posterior probability [PP] of ≥60% by Bayesian analysis with a margin of 1.5 kg – LY2944876 only achieved a PP of 29.4%). Lilly also shared several additional results of interest. At week 24, significantly more patients in the 50 mg dose group had achieved a weight loss of ≥5% body weight (35.5%) than in the placebo (11.8%, p=0.004) or exenatide (18.3%, p=0.025) groups. That said, at week 24, the proportion of participants achieving A1c ≤7% or ≤6.5% in the 50 mg dose group was comparable to that of the exenatide arm. Lilly also reported that fasting glucagon levels were reduced by approximately 40% in the 50 mg group, compared to a ~12% reduction in the exenatide group. There was no significant chance in blood pressure between any of the groups. Heart rate increased in the two highest dose groups for the dual agonist, but the increase was less than the increase observed with exenatide (p<0.05). Adverse events associated with the dual agonist were similar to what might be expected with a selective GLP-1 agonist, largely consisting of GI events.

• Lilly previously partnered with Transition Therapeutics on the development of this candidate, before declining to advance the candidate into phase 3, despite its status as a potential first-to-market GLP-1/glucagon dual agonist. Transition Therapeutics – and this candidate – have since been acquired by OPKO Health, which is investigating a potential obesity indication for this drug, rather than a type 2 diabetes indication. We previously learned that the topline results met the trial’s primary endpoint and demonstrated non-inferiority to exenatide in terms of A1c and superiority in terms of body weight. Full results in hand, however, it’s clear that the weight loss superiority did not meet the predefined criteria that Lilly was looking for. Given its robust portfolio of newly-launched diabetes drugs and early-stage pipeline efforts, Lilly understandably has a very high internal threshold for continued clinical development of its candidates – and particularly for advance into phase 3. Lilly also appears to somewhat favor its internally-developed diabetes candidates to licensed molecules (with the notable exception of the very successful BI alliance, and its acquisition of Locemia’s nasal glucagon). Indeed, Lilly’s phase 1 pipeline includes an internally-developed, once-weekly GLP-1/glucagon dual agonist for type 2 diabetes and NASH, a candidate that was added after the decision not to pursue the Transition Therapeutics partnership further. See our GLP-1/glucagon dual agonist competitive landscape an overview of the robust industry investment in this area.

The Effect of NNC0090-2746, a Dual GIP/GLP-1 Receptor Agonist (RA), on Glycemic Control, Plasma Cholesterol, and Body Weight in Subjects with Type 2 Diabetes: A Phase 2a Randomized Clinical Trial (1071-P)

JP Frias, EJ Bastyr, L Vignati, M Tschöp, C Schmitt, K Owen, RH Christensen, and R DiMarchi

This poster featured phase 2a data deonstrating significant improvements in glycemic control, body weight, and cholesterol with Novo Nordisk’s GIP/GLP-1 receptor agonist NNC0090-2746 compared to placebo after 12 weeks in people with type 2 diabetes. These promising results come on the heels of a separate poster presented at ADA overviewing phase 1 evidence that the candidate is well-tolerated in doses of up to 2 mg in people with type 2 diabetes and can produce meaningful reductions in fasting, post-prandial, and 24 hour profile plasma glucose, as well as A1c reductions of up to 0.67%, after two weeks (1095-P). In this phase 2a study, 108 people with type 2 diabetes (average age 55 years, average A1c 8.3%, average diabetes duration 8 years) were randomized to receive NNC009-2746, placebo, or Novo Nordisk’s GLP-1 agonist Victoza (liraglutide). The Victoza arm was open-label, and this analysis only statistically compares the double-blind NNC009-2746 and placebo arms. After 12 weeks, participants taking the GIP/GLP-1 agonist showed significant improvement in the primary endpoints of A1c reduction: relative to placebo, A1c was reduced 0.63% in the treatment group (95% CI: -0.93 to -0.33; p<0.0001). The GIP/GLP-1 agonist also produced significant reductions in mean 7-point SMPG (-31.7 mg/dl, p<0.0001) and FPG (-38.2 mg/dl, p<0.0001). As for the key secondary endpoint of body weight, NNC009-2746 produced significant weight loss relative to placebo at 8 weeks (-1.8% treatment difference, p=0.0141) but the trend lost significance at week 12 (-1.6%, p<0.05). However, significant improvements were maintained throughout the entire study in various adipose biomarkers and lipid parameters, including total cholesterol (treatment difference -0.92  mg/dl, p=0.02) and plasma leptin levels (treatment difference -0.78 mg/dl, p=0.018). Interestingly, a post-hoc analysis revealed a significant interaction between baseline A1c and body weight reduction such that participants with a baseline A1c  below 8.5% lost significantly more weight with the GIP/GLP-1 agonist relative to placebo than those with an A1c above 8.5% (p for interaction = 0.041), suggesting that the maximum benefit of NNC0090-2746 with respect to weight loss is obtained by people with already near-target glycemic control. As for adverse events, the treatment group experienced more adverse events than the placebo group (65% vs. 42%), driven by a higher proportion of gastrointestinal adverse events (35% vs. 17%) as expected with agents in the GLP-1 agonist family. Together, these results support the safety and efficacy of NNC0090-2746 for impoving glycemic control and reducing body weight (especially for those already with good glycemic control).

ITCA 650 Improves Glycemic Control and Reduces the Need to Advance Antidiabetes Therapy (1078-P)

R Henry, B Schwartz, L Kjems, H Huang, and M Baron

Intarcia presented pooled data from the FREEDOM-1 and FREEDOM-2 clinical trials, to examine the addition of or increase of therapy from baseline as a measure of effectiveness and sustainability of antidiabetes therapy in patients with uncontrolled type 2 diabetes treated with ITCA 650 (n=414), sitagliptin (n=257), or placebo (n=143). Mean baseline A1c for these patients was 8.6% and the criteria for addition of or increase of therapy was predetermined and included an A1c >8.0% after week 26. After data was analyzed up to week 39, results indicated that advancement of therapy was required in 11.8%, 25.7%, and 39.2% of patients treated with ITCA 650, sitagliptin, and placebo respectively. P-values for the comparison between the three groups were not provded.  Additionally, after week 26, the proportion of patients who required therapy advancement increased faster in the placebo and sitagliptin groups compared to the ITCA 650 group. These results suggest that ITCA 650 therapy produces more stable and sustained glycemic control over time than sitagliptin or placebo.

ITCA 650 Significantly Reduces the Need to Advance Antidiabetes Therapy Compared with Sitagliptin (1110-P)

J Rosenstock, P Prabhakar, L Kjems, H Huang, and M Baron

This poster presented an additional exploratory analysis of the FREEDOM-2 trial, which assessed Intarcia’s implantable GLP-1 agonist ITCA 650 (exenatide mini-pump) head-to-head vs. Merck’s DPP-4 inhibitor Januvia (sitagliptin). In FREEDOM -2 study, a randomized, double-blind, double-dummy study, ITCA 650 produced greater reductions in A1c and body weight than sitagliptin. In this analysis, data from patients uncontrolled on metformin (n=263 on ITCA 650, n=257 on sitagliptin; mean baseline A1c 8.6%) was examined to determine the number of patients requiring advancement of antidiabetes therapy. The criteria for addition of or increase of therapy was predetermined and included an A1c >8.0% after week 26. Results demonstrated that only 15% of patients treated with ITCA 650 required therapy intensification at week 26, compared with 35% of patients in the sitagliptin group. After 52 weeks, 85% of those in the ITCA 650 group remained on only 2 therapies (metformin and ITCA 650) compared to almost 65% of patients in the sitagliptin group, indicating better sustained glycemic control and reduced need for additional therapy. These results make a particularly compelling case for ITCA 650 as a second-line therapy for type 2 diabetes and points to a role for ITCA 650 in delaying the need to insulin therapy. Coupled with the weight loss benefits and low risk of hypoglycemia – and with rumors of a lower daily cost compared to injectable GLP-1 agonists already on the market – we can see a convincing argument for the value of ITCA 650 early in the progression of type 2 diabetes.

User Evaluation of the Exenatide Once-Weekly Suspension Autoinjector (1116-P)

S LaRue, J Springer, J Meehan, and C Wysham

This poster provides evidence for the user-friendliness of AZ’s once-weekly exenatide autoinjector. The study involved 104 people unfamiliar with the new autoinjector device, including potential users (people with type 2 diabetes and aregivers), healthcare professionals, and retail pharmacists. These participants were assessed by a human factors professional on 12 critical tasks for which use errors with the autoinjector could possibly result in a negative clinical impact (such as mixing the medication by shaking, removing the needle cap, injecting the dose, etc.). They additionally answered standardized questions on the device’s subjective ease of use using a 5-point scale from “very easy” to “very difficult.” On the first attempt, 78% of participants were able to successfully prepare and complete and autoinjection. Of the minority of participants who were not successful on their first attempt, 42% were able to self-correct and learn from their errors. Furthermore, the success rate for only the essentially tasks considered necessary for medical benefit was above 93%. Together these results support that dosing exenatide with the new autoinjector device is both easily learned and accurate. Submitted for regulatory review in 1Q17, AZ’s exenatide auto-injector fills a vast unmet need by eliminating the complex and lengthy reconstitution process that its Bydureon pen currently requires. A regulatory decision is expected in 2018, and we imagine that, if approved, this new injection device could eliminate one of the biggest barriers to Bydureon uptake.

Symposium: Combination Therapy in Type 2 Diabetes – Promise Delivered?

Pathophysiologic Rationale for Combination vs. Step-Wise Treatment Approach

James Gavin, MD, PhD (Emory University, Atlanta, GA)

In front of a rapt, standing-room-only crowd, the esteemed Dr. James Gavin (Emory University, Atlanta, GA) made an eloquent case for the urgency of combination therapy. He set the stage with an outline of the incredible complexity and heterogeneity of diabetes at both a physiological and genetic level. To illustrate this, Dr. Gavin proposed that diabetes is even more nuanced than the famous “ominous octet” would suggest, presenting an alternative “egregious eleven” which includes the influence of the microbiome, immune system, and increased glucose absorption in the stomach and small intestine in addition to the traditional players – impaired insulin secretion in the beta cells, increased glucagon secretion in the alpha cells, increased hepatic glucose production, neurotransmitter dysfunction, decreased muscular glucose uptake, increased glucose reabsorption in the kidneys, increased lipolysis in adipose tissue, and a decreased incretin effect in the gut. Given this incredible complexity, Dr. Gavin argued that it is imperative to treat diabetes in a more physiologically-minded way; principally (i) prescribing multiple combined diabetes drugs with complementary mechanisms of action to address as many pathophysiological defects as possible, and (ii) doing so early in order to more powerfully delay disease progression and the onset of complications. In an age where so many diabetes drugs are available (several of which, such as GLP-1 agonists and SGLT-2 inhibitors, offer cardioprotective benefits beyond glycemic control), why does the current treat-to-fail paradigm still persist? Dr. Gavin pinpointed this to “conservative” treatment algorithms which “invite clinical inertia” by recommending stepwise treatment. He powerfully exemplified this point by contrasting traditional diabetes treatment algorithms like the ADA’s with the equivalent treatment algorithms for hypertension – another complex and multifactorial disease. Here combination therapy is the mantra of thought – according to Dr. Gavin, hypertension guidelines recommend that as many as 75% of people with hypertension will benefit from initial combination therapy involving drugs with complementary actions. We can only imagine how much better off people with diabetes would be if this philosophy was more embraced in endocrinology practice, although the ongoing issue of access and high drug costs remains an incredibly challenging barrier. A true giant in the field, few people understand the ecosystem of diabetes better than Dr. Gavin, and we left his talk with a sense of optimism that it is possible to push the needle forward in diabetes care.

The Future of Combination Therapy in the Treatment of Type 2 Diabetes – Which Classes, Why, and When?

John Buse, MD (University of North Carolina, Chapel Hill, NC)

Dr. John Buse, a vocal advocate for basal insulin/GLP-1 agonist combinations from the start, suggested that these products (Novo Nordisk’s Xultophy and Sanofi’s Soliqua) should supplant insulin monotherapy as second-line treatment for type 2 diabetes. He highlighted the superior A1c-lowering efficacy, impressive weight loss, and “stunning” reductions in postprandial glucose shown across several clinical studies of Xultophy (insulin degludec/liraglutide) and Soliqua (insulin glargine/lixisenatide). What’s more, these agents are able to get a sizeable proportion of patients to A1c <7% (and ~40% of patients to A1c <6.5%) without inducing hypoglycemia – as Dr. Buse put it, in this danger zone of 0.7%-0.8% A1c-lowering below recommended targets, you’d expect to see an “exploding” increase in hypoglycemia and severe hypoglycemia, but the GLP-1 component of these compounds sidesteps the issue entirely. To further support his position on this particular combo class, Dr. Buse pointed out that the great promise of GLP-1 agonism has always been on a background of insulin. The first paper on GLP-1 in man, published in the NEJM in 1992, investigated the effects of a GLP-1 agonist on top of optimized insulin therapy. In the LEADER trial demonstrating a substantial CV benefit to liraglutide (Novo Nordisk’s Victoza), most patients were taking insulin at baseline. We echo Dr. Buse’s enthusiasm for basal insulin/GLP-1 agonist fixed-ratio combinations, and we’re eager to see greater uptake of Xultophy and Soliqua, which were only FDA-approved seven months ago (coincidentally, on the same afternoon). Pooled sales from these two products totaled $19 million in 1Q17, and we hope to see steep growth for this highly-anticipated and advanced class. We’d also love to see numbers on prescription volume, and will be keeping our fingers crossed for improved reimbursement (since we can’t expect a wide patient population to benefit from these effective new drugs if they aren’t affordable and accessible). To ADA’s credit, basal insulin/GLP-1 combos were swiftly incorporated into the 2017 Standards of Care, which were published <one month after FDA-approval of Xultophy and Soliqua. That said, particularly US-based clinicians as well as payers globally seem to be slow to move to combinations first regardless of the data showing they would benefit from this.

• “I do think there’s a role for SGLT-2 inhibitors in combination with insulin.” Dr. Buse spent part of his talk discussing this potential future direction for combination approaches in type 2 diabetes. He underscored that a majority of patients in EMPA-REG OUTCOME (Lilly/BI’s CVOT for empagliflozin, branded as Jardiance) were taking insulin at baseline, which is suggestive that these two agents can be efficacious and synergistic (though, on the other hand, only about half of participants in the CANVAS program were taking insulin at baseline). There is little guidance for patients/providers right now on how to maximize clinical benefit from a medication regimen incorporating both an SGLT-2 inhibitor and an insulin product, but Dr. Buse hopes for more language on this in upcoming iterations of professional guidelines, and so do we.
• Dr. Buse expressed early excitement for multivalent peptides, including triple combinations of GLP-1/GIP/glucagon. Preclinical investigations in animal models have produced highly-promising data so far, and Dr. Buse especially emphasized how these compounds can optimize weight loss without sacrificing glycemic control (definitely a key consideration in type 2 diabetes care). He characterized this as an up-and-coming area of combination therapy to look out for.
• Moreover, Dr. Buse called attention to a “huge opportunity” for combining a diabetes drug with a weight loss agent – he focused on canagliflozin/phentermine as an example. Phase 2 results from J&J (which markets canagliflozin as SGLT-2 inhibitor Invokana) were presented as a late-breaking poster at ADA 2016, and additional analyses were presented at this meeting. Unlike benefits to A1c, which for a combination therapy are typically less than the sum of reductions from each component monotherapy, Dr. Buse explained that benefits to weight loss can be very close to additive. Indeed, we saw additive weight loss effects for GLP-1 agonist/SGLT-2 inhibitor co-administration in DURATION-8 –  though Dr. Buse was less positive about the glycemic effects of the combination (see below). It’s unclear at the moment whether J&J will move forward with phase 3 studies of canagliflozin/ phentermine, but with such unequivocal support from a thought leader like Dr. Buse, we see a strong case for further clinical development.
• Lastly, Dr. Buse shared some skepticism on GLP-1 agonist/SGLT-2 inhibitor combination approaches. While results from DURATION-8 investigating AZ’s Bydureon (exenatide once-weekly) alongside Farxiga (dapagliflozin) were positive, Dr. Buse emphasized the sub-additive benefits to A1c – “I had hoped for more.” He mentioned the differential effects on glucagon from SGLT-2 inhibitors vs. GLP-1 agonists as one potential concern. On the other hand, Dr. Buse acknowledged that this area of combination treatment holds possibility for aggregate CV benefits. While topline results from the EXSCEL CVOT for exenatide were neutral, other GLP-1 agonists like liraglutide and semaglutide have shown significant cardioprotection, and we’ve now seen CV superiority vs. placebo for two SGLT-2 inhibitors as well – empagliflozin and canagliflozin. Dr. Buse concluded: “Before rushing off and building up GLP-1/SGLT-2 as the clear savior of all patients with diabetes and CV disease, we need to be cautious about understanding this combination better.”

Symposium: Into the Endocrine Bowels of Diabetes

The Incretin Effect – From the Last 30 Years to the Next 30!

Michael Nauck, MD (Diabetes Center, Harz, Germany)

Dr. Michael Nauck provided a comprehensive overview of the incretin effect, looking back at the past 30 years’ work and then looking into the future at upcoming challenges and therapeutic strategies. He opened with a description of the incretin effect is and the mechanisms behind the reduced incretin effect in diabetes, touching on reduced functional beta-cell mass and the loss of response to GIP and/or GLP-1. Moving onto the physiology of GIP and GLP-1, Dr. Nauck also presented arguments for GIP’s role as the “more important physiological incretin hormone,” noting that it reaches higher plasma concentrations after nutrient stimulation and that GLP-1’s gastric emptying slowing effects limit the increment in glucose concentrations following nutrient intake. Assessing the current landscape of incretin-based drugs, Dr. Nauck illustrated that the incretin effect is lost when treated with GLP-1 agonists and that DPP-4 inhibitors similarly do not change the incretin effect. Then looking into the future, Dr. Nauck shared his insights on the challenges for the incretin effect’s experimental paradigm, specifically regarding oral vs. isoglycemic IV glucose, as he noted that assessment of the incretin effect may need to be amended to portal glucose infusion. In addition, he pointed to intra-islet generation of GLP-1 and paracrine stimulation of beta cells as an alternative mechanism explaining the incretin effect. Turning to therapeutic strategies, Dr. Nauck shared that the recovery of an impaired incretin effect in type 2 diabetes may be a good experimental probe to search for GLP-1 secretagogues, as these may serve as new glucose-lowering agents. Lastly, he acknowledged the value of understanding the effects of genetic variants in the incretin system, as these may predict clinical responses to incretin-based therapies – indeed, we agree that personalized medicine is one of the field’s most significant opportunities for the future, though we do not see this quite reaching clinical utility within the next 30 years.

Questions and Answers

Q: What’s the data on metformin and its involvement with GLP-1?

A: I think that’s been studied pretty well. In animal studies, metformin suppresses pro-glucagon, especially in the lower gut. But it doesn’t change the incretin effect. That’s a clear result from the studies.

Q: We’ve always assumed the incretin effect to be hormonal. What are your thoughts on other contributing mechanisms, such as swallowing food or the CNS and neuronal components of the incretin response?

A: The simplest answer is to take type 1 patients and transplant the pancreas. Then you have a fully normal pancreatic effect. That made me believe that the nervous input doesn’t play a big role in the incretin effect.

The Upper Gut and Diabetes

Christopher Rayner, PhD (University of Adelaide, Adelaid, Australia)

Dr. Christopher Rayner discussed the role of the upper gastrointestinal function in postprandial blood glucose control and therapeutic strategies to manipulate gut function. He opened by discussing the importance of postprandial glycemic control and the upper GI tract’s involvement in this process, noting that gastric emptying, secretion of incretin hormones, and small intestinal digestion and absorption are all significant determinants of postprandial glucose. Illustrating the gut’s importance, Dr. Rayner presented a range of data including blood glucose responses to intraduodenal glucose infusion, the effects of gastric emptying on postprandial insulin requirements, as well as the effects of exogenous GLP-1 on blood glucose and plasma insulin levels. As for therapeutic strategies that may help manipulate this gut function, Dr. Rayner focused on short-acting GLP-1 agonists, macronutrient preloads, and suppression of small intestinal motor function. Specifically, he showed data on GLP-1 agonists’ ability to slow gastric emptying and noted that short-acting formulations are likely better for this effect compared to long-acting formulations. In addition, Dr. Rayner presented data on a low-dose whey/guar preload in type 2 diabetes, which demonstrated lower PPG and a ~0.1% A1c reduction over 12 weeks. Lastly, he discussed some data in both human and rat models on GLP-1 agonists’ effects on slowing down small intestinal motility, with demonstrated delays of contents reaching the cecum. From this presentation, we can see the field’s emphasis on the potential of the booming GLP-1 agonist class, as its mechanisms in metabolism from a variety of angles continue to be explored.

Questions and Answers

Q: Could you comment on metformin? It has a multitude of effects, some of which appear to be GI-related.

A: Metformin is a fascinating story. IV dosing of metformin is very effective and dosing to the gut seems to be important. Also, research has shown that dosing to the distal gut seems more important than to the proximal gut. A number of mechanisms could involve the gut – possibly related to GLP-1, bile acids, and the microbiota.

Q: What about the effect of other proteins such as casein on gastric emptying?

A: With the preload strategy, you can choose from different proteins. But the choice of whey protein is made from a series of studies showing slightly favorable effects of whey over other proteins.

Q: You showed that exenatide decreases cecum arrival time. That may explain the constipation of some patients but then why do some patients show diarrhea?

A: You’re right, there’s a variation of reported symptoms. How closely is this related to gut transit? The transit doesn’t seem to correlate well. It looks like stool form may be better correlated with gut transit but it’s an area that is not well understood.

Symposium: Successes with Type 1 Diabetes Complications and Survival

Predictors and Clinical Outcomes of Treatment Intensification in Patients (Pts) with T2D Uncontrolled on Basal Insulin (BI) in Real-World Settings

Lee Kallenbach, PhD (Practice Fusion, San Francisco, CA)

In patients with uncontrolled type 2 diabetes, treatment intensification with GLP-1 agonist/basal insulin co-administration leads to significant A1C reductions and lower rates of hypoglycemia vs. patients who have no treatment modifications. Dr. Lee Kallenbach discussed these results, and put them in context with therapeutic inertia and a reluctance to consider combination agents in type 2 diabetes care. HCPs too-often delay intensification of treatment for patients with uncontrolled type 2 diabetes who have not achieved their glycemic goals (A1c <7% after six months on basal insulin), which is a barrier to optimal care. Using data collected from January 2011-December 2013 in Practice Fusion’s EHR system, Dr. Kallenbach reported that only 2,121 out of 14,653 patients (a meager 14%) intensified their basal insulin regimen within six months. Those who did intensify did so with a rapid-acting insulin, with a GLP-1 agonist, or with another injectable therapy. Mean A1c-lowering was greater in all three injectable therapy groups vs. controls who did not add another medication to their basal insulin monotherapy: After 12 months and from a baseline A1c ~9%, A1c declined 0.3% in the rapid-acting insulin arm, 0.3% in the GLP-1 arm, 0.2% in the “other” category, and 0.1% in the control category. Patients adding a GLP-1 agonist experienced the lowest rates of hypoglycemia of all study participants. Dr. Kallenbach concluded that intensifying basal insulin treatment by adding a GLP-1 agonist may have profound beneficial effects in patients with type 2 diabetes.

Corporate Symposium: Novel Approaches to Improving Adherence in T2D (Sponsored by Intarcia)

How Does Adherence Impact Patient Outcomes?

Steve Edelman, MD (UCSD, San Diego, CA)

Dr. Steve Edelman gave a passionate talk on the role of adherence in improving outcomes in type 2 diabetes. Despite the approval of 40 new type 2 diabetes drugs over the past decade, there has been no increase in the proportion of patients with an A1c <7% (~50% of patients) and no decrease in the proportion of patients with an A1c >9% (~30% of patients). Dr. Edelman highlighted the unacceptable current levels of morbidity and mortality due to type 2 diabetes and the soaring costs of treatment, noting that 43% of diabetes spending goes toward inpatient treatment vs. only 12% to therapies and devices (“this really bothers me”). Dr. Edelman attributed this bleak state of affairs to the enormous gap between results in clinical trials and those in the real world. He cited an analysis demonstrating that comparable patients get only half the A1c reduction from GLP-1 agonists in the real world as they do in clinical trials and that 75% of this gap is due to adherence. He emphasized that this problem is not unique to GLP-1 agonists or other injectable medications, since oral type 2 diabetes therapies also have adherence rates below 50%. Dr. Edelman described poor adherence as the result of an imbalance between the perceived costs of taking medications (adverse effects, concerns about long-term effects, being labeled as sick) and the perceived benefits (patients don’t feel any different). He stressed that the most important way clinicians can make a dent in this problem is by truly listening to their patients and asking them open-ended questions about their challenges with diabetes management.

• Dr. Edelman listed three questions that clinicians should ask their patients during a visit:
  
  • (i) What is the hardest thing for you about managing your diabetes?
  • (ii) How often do you forget to take your medications?
  • (iii) Do you have any concerns or fears about your medications?
• Dr. Edelman told a story that was particularly illustrative of the need for real trust between doctors and patients. He described a patient of his who was taking five different medications for type 2 diabetes, including over 200 units of insulin per day, yet had an A1c consistently above 13%. Taking her at her word that she was taking her medications as prescribed, Dr. Edelman continued raising her doses, until one day he decided to give her 25 units of insulin aspart in the clinic (normally taking up to 80 units by history from the patient) to observe her response himself. The patient’s blood glucose dropped dramatically, to the point where she experienced severe hypoglycemia requiring a code to be called. After this, the patient admitted that she was afraid of taking insulin but didn’t want to disappoint her doctors, so she filled every prescription but had not actually taken any of the medication. This anecdote was an excellent reminder that HCPs not only need to go down their checklist and ask all the right questions (“are you taking your medications?”), but that they need to create an environment where patients trust them enough to provide honest answers.

Injectable GLP-1 RA Therapy in T2D: Benefits and Downfalls

Julio Rosenstock, MD (University of Texas, Dallas, TX)

Dr. Rosenstock delivered a broad overview of injectable GLP-1 agonist therapy and how both evidence and clinical experience have expanded rapidly in the field. He reviewed the major physiologic actions of GLP-1 agonists, including increasing glucose-dependent insulin secretion and lowered glucagon secretion, increased satiety, and effects on gastric emptying and GI adverse events. He also provided an overview of the differentiation of different GLP-1 agonists in source, dose frequency, pharmacokinetics, receptor agonism, and main glycemic target. Most notably, he drew a distinction between “prandial” GLP-1 agonists from “non-prandial” GLP-1 agonists. Short-acting, prandial GLP-1 agonists tend to have a strong reduction on post-prandial glucose, reduce post-prandial insulin secretion and glucagon, and decelerate gastric emptying rate. Non-prandial, or long-acting, GLP-1 agonists have more stable plasma levels over 24 hours with a predominant effect on FPG and little to no effect on gastric emptying.

• Dr. Rosenstock characterized LEADER as a “gamechanger” in terms of proving cardiovascular benefit in patients with proven cardiovascular disease. He highlighted the role these results – demonstrating a CV benefit for liraglutide – could have on the positioning of GLP-1 agonists within the diabetes armamentarium in the real world. Currently, GLP-1 agonists are prescribed as second or third line therapy with orals with or without basal insulin and Dr. Rosenstock suggested that prescribing may increase due to this evidence of  additional cardiovascular benefits. In fact, he even suggested that GLP-1 agonists could be be positioned as a second line therapy after metformin.
• In an overview of the major trials on GLP-1 agonist efficacy among different agonists, he illustrated the benefit-risk profile for these agents. Although there is a range, he indicated that GLP-1 agonists were comparable for the most part in A1c and body weight efficacy. However, the class still struggles with barriers such as GI adverse events and injectable administration, which may be reasons for the slow growth, inconsistent adherence, and low treatment persistence with frequent drug discontinuations. The adverse effects are well known, with major issues including nausea, vomiting, diarrhea, and hypoglycemia when associated with insulin. However, the nausea and vomiting are worse initially but subside, and only 3%-5% of patients cite them as the reason for treatment withdrawals. However, Dr. Rosenstock pointed out that, in the real world, the withdrawal rate is around 40%-50% because patients do not receive the same support. Factors affecting choice and persistence include injection frequency, needle size, injection-site reactions, GI side effects, and the cost. Overall, he emphasized that strategies to overcome these barriers are needed to address the many adherence issues present with GLP-1 agonist use.

Novel Approaches to GLP-1 RA Delivery: Improving Adherence and Patient Outcomes

Robert Henry, MD (UCSD, San Diego, CA)

Dr. Robert Henry reviewed the current phase 3 data on Intarcia’s ITCA 650, portraying it as the next step needed to make GLP-1 agonists a standard second-line or possibly even first-line treatment for type 2 diabetes. He discussed i) the FREEDOM-1 study that demonstrated statistically superior A1c reductions of 1.%4-1.7% after 39 weeks with ITCA 650 vs. placebo; ii) the FREEDOM-1 HBL study that demonstrated a mean A1c reduction of 3.4% with ITCA 650 in patients with a higher baseline A1c (10%-12%); and iii) the FREEDOM-2 study that demonstrated significantly greater A1c reductions (1.5% vs. 0.8%) and weight loss (4 kg vs. 1.3 kg) with ITCA 650 vs. Merck’s Januvia (sitagliptin). Interestingly, he did not mention the FREEDOM-CVO study that demonstrated non-inferiority on cardiovascular outcomes with ITCA 650 vs. placebo – there has been very little mention of this study since the topline results were released over a year ago (May 2016), and we have yet to see full results from the trial which is unusual given the high level of anticipation for CVOT results in the diabetes field. Dr. Henry concluded by emphasizing Intarcia’s efforts to make the implantation procedure as simple as possible and describing ITCA 650 as a potential game changer. This is the very first time Intarcia has sponsored a corporate symposium to our knowledge and we’re very glad to see its success. The ensuing panel discussion underscored both the novelty of ITCA 650 for many healthcare providers and the interest the concept of implantable therapy generates – see below.

Questions and Answers

Q: Is ITCA 650 considered a short-acting or long-acting GLP-1 agonist?

Dr. Rosenstock: It is long-acting. You’re taking exenatide subcutaneously and it clears in 3 min so it has a really short biologic activity and short half-life. Here you have continuous levels of a GLP-1 agonist, which is more continuous than exenatide once-weekly, which has big spikes. And probably those weekly injections eventually level off. This is a short acting GLP-1 agonist molecule that is used as a continuous infusion just like an insulin pump.

Q: Why do you expect adherence with ITCA 650 in the real world to be higher than other GLP-1s and why can’t the patient remove the device?

Dr. Steven Edelman (UCSD, San Diego, CA): You saw the percentage of dropouts due to nausea and it was very darn low. I expect adherence to be basically 100% except for the very small number of patients who have unusual nausea. I think we’ll see the real impressiveness of this device when they do real-world studies. If you look at A1c reductions vs. other GLP-1s, they’re in a comparable range in the clinical trial setting. You saw the data on persistence and adherence. I think the beauty will be when it gets out to real world.

Dr. Rosenstock: Patients cannot remove the device themselves. If it needs to be removed, they have to go and have it removed by a professional.

Dr. John Anderson (Frist Clinic, Nashville, TN): It’s easy with an injectable to skip the next dose when you have GI side effects. When you have an implantable device, you’ll push through more. If you really want it removed, you have to make an appointment. I think people will be more willing to tolerate transient GI side effects.

Dr. Rosenstock: What we know from the one-year data is that eventually the nausea subsides. 3%-5% have it. There’s some relapse if people overeat, etc. Here patients will hang in there. They don’t have the option to take it out unless they call.

Dr. Anderson: I think people will feel more investment in having something subcutaneous. It’s almost like being in a trial.

Q: What would be the possible barriers to starting patients on this therapy, assuming it is approved?

Dr. Edelman: The only barrier I foresee is the initial discussion with the patient and how you discuss it with them to frame it correctly. I don’t suggest using the word surgery or words that scare patients. For me, the first barrier is getting their buy-in. After that it’s pretty easy.

Dr. Anderson: It’s important to show them the device. When you look at the matchstick it’s very subtle and it’s not going to be seen.

Dr. Henry: You’ll ask some patients how it is and they’ll forget they have it in. They have amazing control but they’ll forget it’s coming from the ITCA 650

Q: How are healthcare providers going to be trained on the procedure?

Dr. Henry: Intarcia has a training program where people will go and train providers to insert and remove the device.

Dr. Anderson: If you don’t want to do this yourself in primary care, Intarcia has plans to train people to be in your region and do it for you. It shouldn’t be a barrier if you yourself don’t want to train.

Q: How much will it cost?

Dr. Henry: I don’t know. I think it will be very reasonable and hopefully one of the less expensive GLP-1s. We’ll have to wait and see.

Dr. Edelman: Talking to payers, one thing that’s very important to them is adherence. If person is adherent, you may be paying more for the price of the prescriptions, but when they analyze the cost savings of reduced hospitalizations, absenteeism, disability claims, there are incredible benefits when patients are adherent. You spend a little more in terms of medications but you probably save 20-40x that in health benefits. I think payers will be very attracted to this.

Dr. Henry: 100% adherence has to translate to fewer complications.

Q: How do you adjust the dose from 20 to 60 mg per day?

Dr. Rosenstock: This has been tested where you always start with 20 mg as the priming dose and lowest dose to get people adjusted. After 3 months you can go up to 60 mg. We showed a study going from 20 to 40, 20 to 60, and 20 to 80, which had more GI side effects, and between 20 to 60, which shows better weight loss. When you have nausea that subsides after 20 mg, when going up to 60 mg you get a little spike of nausea and which then goes down. You can put the 60 mg device in the same place as where you put the 20 mg so it is in the same spot and doesn’t require multiple insertion areas. The key issue here is we have to make life much simpler for the patients. John presented a case that goes from metformin to ITCA 650. I think the patient could be on an SGLT-2 inhibitor before adding the ITCA 650 device. Metformin, SGLT-2 inhibitors, and GLP-1 agonists would be a good combination and if you did this earlier I bet you could control 80%-90% of people with type 2 diabetes and you would be done.

Dr. Edelman: Can you talk about other therapies that might be worked on to put in this device?

Dr. Henry: Intarcia is actively looking at other compounds. Not every compound can go in the device. It has to have a small volume and be stabilized. Clearly there are many peptides and maybe non-peptides that could go in the device. Perhaps anti-tumor medications, anti inflammatories. There are many areas for the future.

Dr. Edelman: The Gates Foundation is working with Intarcia to develop a treatment for HIV in Africa.

Dr. Rosenstock: This is totally different from what we’ve done before in diabetes. I think it’s a game-changing concept. It may facilitate intervening much earlier in much healthier patients. When people are much healthier, they don’t want to take medications. They want to stay healthy but they don’t want to take pills or injections.

Dr. Henry: The potential for game changing is real. I hope it’s approved soon and the market takes it up. It’s a great opportunity for sustained, effective glucose control and weight loss.

Corporate Symposium: Optimizing Comprehensive Glycemic Management in Challenging Patients with Type 2 Diabetes (Sponsored by Sanofi)

Vanita Aroda, MD (MedStar Health Research Institute, Hyattsville, MD), Lawrence Blonde, MD (Ochsner Medical Center, New Orleans, LA), Vivian Fonseca, MD (Tulane University Health Sciences Center, New Orleans, LA), and Juan Frias, MD (UCLA, Los Angeles, CA)

This Sanofi-sponsored corporate symposium highlighted the potential of basal insulin/GLP-1 agonist fixed-dose combinations as an optimal therapeutic options for patients not achieving their goals on basal insulin alone. Dr. Vivian Fonseca kicked off the symposium with an overview of current treatment options, the need for therapies that help patients achieve glycemic goals with minimal hypoglycemia and weight gain, and the importance of the patient-oriented perspective on minimizing injections and daily burdens of therapies. Dr. Vanita Aroda then discussed the importance of addressing postprandial glucose (PPG) as an integral part of treatment to lower A1c. PPG may also be tied to cardiovascular risk, although trial data has been mixed. She examined both short- and long-acting GLP-1 agonists and their differing effects on PPG, finding that short-acting GLP-1 agonists like exenatide and lixisenatide flattened PPG glucose levels significantly while long-acting liraglutide predominantly  showed lowering of FPG with some improvement in  PPG. Dr. Blonde then led a review of the treatment options in type 2 diabetes and the use of basal insulin as the first choice injectable therapy recommended by the ADA and AACE. Interestingly, in a series of five studies investigating basal insulin as the first injectable, GLP-1 agonists were found to be more effective in A1c reduction and additionally helped with weight loss, although GLP-1 agonists are not currently a first line therapy according to the dominant treatment algorithms in the US. Dr. Blonde also reviewed the impact of hypoglycemia in insulin use, which is a key challenge for patients and a common reason cited for patients who choose to discontinue insulin. Newer insulins like Novo Nordisk’s Tresiba (insulin degludec) or Sanofi’s Toujeo (insulin glargine U300) are associated with similar A1c and weight reductions as older insulins but also have the additional benefits of lowering the risk for both nocturnal and severe hypoglycemia, as demonstrated  in trials like SWITCH 2 and EDITION 1, 2, and 3. However, Dr. Blonde pointed out that many patients will not attain or maintain target glycemia with basal insulin alone, and there are further strategies for intensification depending on the patient’s profile. When on the lower end of the A1c spectrum, hyperglycemia may be driven more by PPG and can be addressed by combination injectable therapy. To conclude the symposium, Dr. Juan Frias knitted everything together with a broad overview of the complementary mechanisms of action between basal insulin and GLP-1 agonists on insulin release, glucose uptake, glucose production, glucagon secretion, and gastric emptying. The two major fixed-dose combinations – Sanofi’s Soliqua (insulin glargine/lixisenatide) and Novo Nordisk’s Xultophy (insulin degludec/liraglutide) - are approved in the US for patients suboptimally controlled on any basal insulin or lixisenatide and/or liraglutide in combination with any oral medication. However, in Europe these agents have more expansive labels approved as the first injectable agent. The benefits of a fixed-ratio combination compared to individual components is compelling – improved glycemic control, a body weight benefit, no increase hypoglycemia, and reduced GI side effects.

Questions and Answers

Q: Some patients stop responding to GLP-1 agonists. Can you explain why this happens and how to address it?

Dr. Fonseca: Some people just stop taking the medication and you need to have a frank discussion about that. Secondly, you wonder about the development of antibodies, particularly with exenatide. Neutralizing antibodies are not that common in GLP-1 agonists except in exenatide. In that case, you can stop the drug and switch to another GLP-1 agonist and see what happens. Thirdly, it is possible to use GLP-1 agonists inappropriately because the patient lacks insulin. If you’re insulin deficient, nothing is going to work.

Dr. Frias: Secondary failure is the nature of type 2 diabetes management. At some point you reach an equilibrium or your diabetes progresses.

Q: It seems like we are giving our patients all of these drugs, but not reaching our goals. What else can you do?

Dr. Aroda: We keep treating to failure and we need to prevent that.

Dr. Blonde: There are studies that show earlier treatment with combinations of agents may produce more durable reductions in A1c. It would be interesting to do a study in coformulations that looks at simultaneous versus sequential therapy. There are studies that suggest simultaneous is better than sequential.

Q: You use U500, the maximal amount of insulin. What do you do when someone needs more than that?

Dr. Blonde: Well you’ve got to treat the patient. If they need more insulin then give it to them, but you should also be asking why the maximum amount of basal is not working. And maybe you should consider bariatric surgery or something of the like to handle this.

Q:  The ideal combo would be U300 and lixisenatide for a lot of patients. Why wouldn’t you use this?

Dr. Fonseca: Well the simple answer is that you can’t give test two experimental agents at the same time and these two drugs were in the experimental process at the same time so you can’t do that right now. The FDA won’t let you do that. But in the future you may see that there are trials around this and while I don’t like to predict the future often, you could see this coming sometime soon. 

DPP-4 Inhibitors

Oral Presentations: Landscape of Therapeutic Trials in Type 2 Diabetes

Safety and Efficacy of Ertugliflozin Plus Sitagliptin vs. Either Treatment Alone after 52 Weeks in Subjects with T2DM Inadequately Controlled on Metformin: VERTIS FACTORIAL Trial Extension

Richard Pratley, MD (Florida Diabetes and Endocrine Center, Orlando, FL)

Dr. Richard Pratley shared one-year findings from the VERTIS FACTORIAL trial, underscoring the glucose-lowering and weight loss efficacy of Merck/Pfizer’s SGLT-2 inhibitor ertugliflozin in combination with sitagliptin (Merck’s DPP-4 inhibitor Januvia). This is particularly exciting as we await FDA decisions on ertugliflozin, ertugliflozin/metformin (fixed-dose combination), and ertugliflozin/sitagliptin (fixed-dose combination) expected by January 2018 – we’ve been looking forward to this data for a long time! In VERTIS FACTORIAL, 1,233 patients with type 2 diabetes on stable metformin therapy were randomized to one of five arms: (i) a 5 mg dose of ertugliflozin, (ii) a 15 mg dose of ertugliflozin, (iii) a 100 mg dose of sitagliptin, (iv) a combination regimen of 5 mg ertugliflozin/100 mg sitagliptin, or (v) a combination regimen of 15 mg ertugliflozin/100 mg sitagliptin. Initial 26-week results were presented in a poster at EASD 2016, and Dr. Pratley discussed data from the trial extension out to 52 weeks, which demonstrated sustained superior reductions in A1c and fasting plasma glucose for the SGLT-2/DPP-4 combinations vs. either agent alone. After one year of treatment, A1c dropped by 1.4% from a baseline 8.6% for both the combo therapy groups vs. an A1c decline of 1%, 0.9%, and 0.8% for the 5 mg ertugliflozin, 15 mg ertugliflozin, and 100 mg sitagliptin groups, respectively (and that’s in an RCT – unlikely that would be seen in “real life” from our admittedly speculative view). The treatment difference for A1c decline was statistically significant in favor of the combination vs. either monotherapy in all comparisons (p<0.05). In both combo arms, 40% of participants reached an A1c goal of <7% after one year vs. 26% of patients on 5 mg ertugliflozin, 23% of patients on 15 mg ertugliflozin, and 27% of patients on sitagliptin. A “global” word on findings such as these – we’d love to see what the A1c goals would look like with other interventions combined after the initial findings (diet, exercise, behavior modification, peer to peer counseling, etc.)

• Ertugliflozin also demonstrated a profound weight loss benefit in VERTIS FACTORIAL. Dr. Pratley showed that ertugliflozin was associated with 2.4 kg (5.3 lbs) weight loss at a 5 mg dose, 3.2 kg (7.1 lbs) weight loss at a 15 mg dose, 2.4 kg (5.3 lbs) weight loss at a 5 mg dose in combination with sitagliptin, and 2.8 kg (6.2 lbs) weight loss at a 15 mg dose in combination with sitagliptin. Meanwhile, patients on sitagliptin alone in VERTIS FACTORIAL experienced 0.1 kg (0.22 lbs) weight loss on average over the course of a full year. Baseline body weight was 87 kg-89 kg (192 lbs-196 lbs) across all study arms. Weight loss is one of the key aspects to SGLT-2 inhibitors that makes these products so appealing for type 2 diabetes patients (not to mention the superior A1c-lowering and possible CV benefits). We’re not at all surprised to see marked improvements in body weight with ertugliflozin treatment vs. sitagliptin or placebo, but we’re always happy to see corroborating evidence on this front. We’re also pleased to see that combination with sitagliptin does not appear to substantially attenuate the weight loss effect of ertugliflozin.
• Dr. Pratley’s presentation highlighted SGLT-2/DPP-4 fixed-dose combination tablets as an important advancement in type 2 diabetes care. He began with the statement that SGLT-2 inhibitors and DPP-4 inhibitors have complementary mechanisms of action, which suggests that a combination of the two could be a more efficient way to get patients to goal – especially those with high baseline A1c. VERTIS FACTORIAL provides hard evidence for the benefits to this particular combination vs. either monotherapy, with more patients getting to A1c goal while also losing weight and facing a lower pill burden.

Safety and Efficacy of Ertugliflozin after 52 Weeks in Subjects with T2DM Inadequately Controlled on Metformin and Sitagliptin: Results from the Extension Phase of the VERTIS SITA2 Trial

Jie Liu, MD (Merck & Co., Chicago, IL)

Dr. Liu presented 52-week results from VERTIS SITA2 investigating ertugliflozin as an add-on to a metformin/sitagliptin regimen – a follow-up to the 26-week data shared in an oral presentation at EASD 2016. Participants (n=464) with type 2 diabetes experienced a mean 0.8% A1c decline from a baseline of 8.1% with 5 mg ertugliflozin after one year, while patients in the placebo arm showed essentially flat A1c from baseline 8% (p<0.05). Similarly, people randomized to 15 mg ertugliflozin experienced a mean 0.8% A1c reduction from a baseline of 8% (p<0.05 vs. placebo). Dr. Liu displayed graphs to clearly depict this sustained glucose-lowering effect out to one year, which is certainly compelling, in our view. In VERTIS SITA2, 33% of patients on ertugliflozin reached an A1c target <7% at week 52, regardless of dose, compared to only 14% of the placebo group. We’re glad to see such strong data from the VERTIS program, and we’re excited by the prospect of a fourth SGLT-2 inhibitor coming soon to the commercial market by a group that could more successfully get this class to the patients that need it. Expanded options within this class will be a noteworthy win, and we look forward to seeing how ertugliflozin may grow whole class sales – while patients and clinicians in the US are rarely “choosing” compounds anymore, as much as the formularies are making choices for them, we do believe that a powerhouse combo of Merck/Pfizer marketing in this class would be positive for all.

• Weight loss effects were consistent between week 26 and week 52 in VERTIS SITA2. According to Dr. Liu, body weight decreased by a mean 3.5 kg (7.7 lbs) from a baseline 88 kg (194 lbs) for the 5 mg ertugliflozin group, by a mean 2.8 kg (6.2 lbs) from a baseline 87 kg (192 lbs) the 15 mg ertugliflozin group, and by 1 kg (2.2 lbs) from a baseline 87 kg (192 lbs) for the placebo group.
• As Dr. Liu put it, DPP-4 inhibitors are already commonly considered as a second-line therapy option after metformin, and this data now supports earlier intervention with an SGLT-2 inhibitor alongside. Merck’s Januvia (sitagliptin) leads the DPP-4 inhibitor class in sales and has surely cultivated familiarity among diabetes care providers, so we’re hopeful that a fixed-dose combination of ertugliflozin/sitagliptin – if approved – also becomes an early consideration for type 2 diabetes treatment. That said, frustratingly in the US, clinicians and payers seem to be less comfortable with fixed dose combinations than do their counterparts in other geographic regions. We’d love to get more patient sentiments, particularly that relate to adherence, to the payers.

Oral Presentations: Translating Therapeutics to the Real World

Subclasses of Dipeptidyl Peptidase-4 Inhibitors and Cardiovascular Risk: Analysis of Real-World Data for 747,392 Patients with Type 2 Diabetes

Kyoung Hwa Ha, MD (Ajou University School of Medicine, Suwon, South Korea)

Dr. Kyoung Hwa Ha presented data from the claims database of the Korean National Health Insurance System, comparing the risk of cardiovascular disease associated with five different DPP-4 inhibitors in Korean patients with type 2 diabetes. Specifically, the study identified 747,392 patients who used sitagliptin (n=232,855), vildagliptin (n=98,368), saxagliptin (n=44,422), linagliptin (n=299,294) or gemigliptin (n=72,453) between January 2013 and June 2015. According to the results, the observed numbers of CVD events (coronary artery disease, heart failure, stroke, or transient ischemic attack) were 13,627 (291,363 person-years) for sitagliptin, 6,676 (122,529 person-years) for vildagliptin, 2,353 (52,028 person-years) for saxagliptin, 18,972 (402,492 person-years) for linagliptin, and 4,027 (79,904 person-years) for gemigliptin users. Compared to sitagliptin, the fully adjusted hazard ratios for CVD events were 1.05 (95% CI: 1.02-1.08; p = 0.001) for vildagliptin, 0.93 (95% CI: 0.89-0.97; p = 0.001) for saxagliptin, 0.93 (95% CI: 0.91-0.95; p< 0.001) for linagliptin, and 0.96 (95% CI: 0.93-1.00; p = 0.039) for gemigliptin. Thus, Dr. Ha concluded that vildagliptin therapy may be associated with higher risk of CV events, while therapy with sitagliptin, saxagliptin, linagliptin, and gemigliptin were associated with lower CV risk.

Posters

Combination Therapy of Canagliflozin and Teneligliptin in Japanese Patients with T2DM: Results from Phase 3 Studies (1194-P)

K Kaku, T Kadowaki, N Inagaki, K Kondo, K Nishimura, G Kaneko, N Maruyama, N Nakanishi, H Iijima, Y Watanabe, and M Gouda

This poster displayed an integrated analysis of three phase 3 studies comparing canagliflozin/teneligliptin co-administration vs. monotherapy with either the SGLT-2 inhibitor (canagliflozin) or the DPP-4 inhibitor (teneligliptin). Two 24-week trials randomized Japanese participants with type 2 diabetes to canagliflozin vs. placebo as an add-on to a background of teneligliptin (n=138), or to teneligliptin vs. placebo as an add-on to a background of canagliflozin (n=154). Both studies showed superior A1c-lowering with the SGLT-2/DPP-4 combination vs. either agent alone: In the former, the A1c treatment difference was 0.88% in favor of canagliflozin (p<0.001 vs. placebo), dropping from a baseline A1c ~8%. In the latter, the A1c treatment difference was 0.94% in favor of teneligliptin (p<0.001 vs. placebo), also from a baseline A1c ~8%. A third, 52-week open label trial added canagliflozin onto a baseline regimen of teneligliptin (n=153). Sustained A1c improvements on combination therapy were observed throughout the one-year trial duration, and 82% of participants achieved clinically-meaningful A1c reductions and body weight reductions. This highlights one of the key benefits to SGLT-2/DPP-4 combos, in that they show superior glucose-lowering efficacy and weight loss efficacy, all the while offering a milder side-effect profile vs. either drug alone. Indeed, adverse events were well balanced across all groups, with the exception of genital mycotic infections which are expected to be higher with SGLT-2 inhibitor treatment (occurring in 1% of male trial participants and 11% of female trial participants in the third, 52-week study). These integrated results were the basis for a New Drug Application jointly-submitted by Mitsubishi Tanabe Pharma (which markets canagliflozin in Japan as Canaglu) and Daiichi Sankyo (which markets teneligliptin as Tenelia) to Japanese regulatory authorities earlier this year. A decision on this fixed-dose combination candidate, MT-2412, is expected in 2Q18.

Safety and Efficacy of Ertugliflozin in Combination with Sitagliptin in Subjects with T2DM Inadequately Controlled on Diet and Exercise: The VERTIS SITA Trial (1197-P)

B Lauring, S Miller, T Krumins, H Zhou, S Huyck, J Johnson, G Golm, S Terra, J Mancuso, and S Engel

This poster displayed 26-week results from Merck/Pfizer’s VERTIS SITA trial comparing combination therapy with SGLT-2 ertugliflozin/DPP-4 inhibitor sitagliptin (Merck’s Januvia) vs. placebo. The study randomized participants (n=254 patients with type 2 diabetes who completed the entire duration of the trial on medication) to one of three arms: (i) 5 mg ertugliflozin/100 mg sitagliptin once-daily, (ii) 15 mg ertugliflozin/100 mg sitagliptin once-daily, or (iii) placebo. Patients in the lower dose combo group experienced a mean A1c reduction of 1.6% from a baseline 8.9% vs. a mean A1c reduction of 0.44% from a baseline of 9% for patients on placebo (p<0.001). Similarly, patients in the higher dose combo group experienced superior A1c reductions of 1.68% from a baseline 9% (p<0.001 vs. placebo). Defining A1c goal as <7%, 36% of 5 mg ertugliflozin participants and 31% of 15 mg ertugliflozin participants achieved this target by week 26 vs. only 8% of placebo participants (p<0.001 for both comparisons). The dual therapy was also associated with significant reductions in weight and systolic blood pressure. On average, body weight dropped 2.9 kg (6.4 lbs) for people on 5 mg ertugliflozin/100 mg sitagliptin vs. 0.9 kg (2 lbs) for people on placebo (p<0.001). Patients on 15 mg ertugliflozin/100 mg sitagliptin lost a mean 3 kg (6.6 lbs) over 26 weeks (p<0.001 vs. placebo). Baseline body weight was 91 kg (201 lbs) in the two dual therapy arms and was 95 kg (209 lbs) in the placebo arm. Systolic blood pressure declined by 2 mmHg in the lower dose combo group and by 4 mmHg in the higher dose combo group, but actually increased by a mean 2.4 mmHg among patients on placebo (p=0.011 and p<0.001, respectively). This trial saw little difference in adverse events across groups (and a generally low incidence of safety issues overall) as well as great retention – 291 were randomized, 282 completed all 26 weeks, and 254 completed on study medication. Fewer participants (~2% of both ertugliflozin/sitagliptin groups) discontinued treatment vs. placebo (~3%). Ultimately, in patients with type 2 diabetes not at goal, co-initiation of ertugliflozin and sitagliptin could provide better glycemic control, weight loss, and lower blood pressure.

• These poster results were part of a range of VERTIS program studies presented at this ADA (also VERTIS MONO, VERTIS SITA2, and VERTIS FACTORIAL). Across the board, these posters and oral presentations emphasized the value of a fixed-dose SGLT-2/DPP-4 combination due to superior glucose-lowering, weight loss, and blood pressure-lowering efficacy. If approved by the FDA (and decisions on standalone ertugliflozin as well as this fixed-dose combination and a fixed-dose combination of ertugliflozin/metformin are expected by January 2018), this new oral combination will join a class with AZ’s Qtern (dapagliflozin/saxagliptin) and Lilly/BI’s Glyxambi (empagliflozin/linagliptin). We’re eager to see this approval, as we see the Merck/Pfizer duo as particularly fit to make a fixed-dose SGLT-2/DPP-4 combination a commercial success and to ensure wide patient access.

Product Theaters

Impact of the Incretin System on the Treatment of Type 2 Diabetes (Sponsored by Merck)

Zachary Bloomgarden, MD (Mount Sinai School of Medicine, New York, NY)

Dr. Zachary Bloomgarden led this product theater focused on Merck’s DPP-4 inhibitor Januvia (sitagliptin), and more broadly, discussed the role of the incretin system in type 2 diabetes. He opened the session by highlighting the reduced incretin effect in type 2 diabetes – in healthy individuals, the incretin effect would be augmented in response to higher glucose levels, but this response is impaired in type 2 diabetes pathophysiology. In addition, type 2 diabetes is associated with impaired suppression of alpha-cell glucagon, which contributes to postprandial hyperglycemia. With this background, Dr. Bloomgarden illustrated the mechanisms of action of incretin hormones and then reviewed the use of Januvia and Janumet (sitagliptin/metformin fixed-dose combination) in type 2 diabetes management. Throughout the product theater, he mentioned much data from the sitagliptin clinical program, highlighting the ability of these drugs to enhance active incretin levels and to restore insulin secretory responses in combination with metformin. Dr. Bloomgarden also reviewed Januvia’s and Janumet’s adverse event profiles and important risk information for prescribers.

Novel Therapies

Oral Presentations: ADA Presidents Oral Session

REMD-477, a Human Glucagon Receptor (GCGR) Antibody, Reduces Daily Insulin Requirements and Improves Glycemic Control in People with Type 1 Diabetes (T1D)

Jeremy Pettus, MD (UCSD, San Diego, CA)

Dr. Jeremy Pettus presented exciting phase 1 data demonstrating that a single dose of the human glucagon receptor (GCGR) antibody REMD-477 can produce substantial and long-lasting (weeks!) reductions in insulin requirements and improvements in glycemia and time-in-range in people with type 1 diabetes, without increasing hypoglycemia. In a double-blind study, people with type 1 diabetes (n=21) were randomized to receive a single subcutaneous injection of either 70 mg REMD-477 or placebo. One day following the injection, participants who received REMD-477 experienced a significant 21% reduction (9 units) in daily insulin dose compared to those who received placebo (p=0.02); this intensified to a 26% reduction (12 units) by the second day after the injection (p=0.02).  Furthermore, REMD-477 produced substantial reductions in average daily blood glucose concentration not days but weeks after the injection. For people in the treatment arm, average glucose fell 27 mg/dl in the first week post-injection (p<0.0010), -31 mg/dl in the second week (p=0.05), and -20 mg/dl in the third week (p=0.05). REMD-477 further produced substantial increases in time-in-range. In the week following the injection, participants on REMD-477 spent 71% of their time in normoglycemia (70-180 mg/dl), versus 56% for those on placebo (p=0.0001), and the effect persisted into the second week post-injection (70% time-in-range with REMD-477, versus 57%; p<0.05). This increased time spent in normoglycemia with REMD-477 was driven by reductions in hyperglycemia; importantly, hypoglycemia did not increase with REMD-477. Although the mechanism of action of this candidate is not yet understood, Dr. Pettus presented evidence that a single dose of REMD-477 produces long lasting elevations in plasma glucagon and GLP-1 that don’t return to baseline until 57 post-injection. Adverse events were infrequent and minor (headache, oropharyngeal pain, etc.) and did not substantially differ between the REMT-477 and placebo groups (11 vs. 10 events), indicating a good safety profile for this candidate. We are very moved by the sheer timescale of REMD-477’s powerful actions and eager to learn more about the upcoming phase 2 study, which according to Dr. Pettus will examine the effect of multiple weekly doses of the peptide drug. For good reason Dr. Pettus’ presentation was certainly one of the most highly-anticipated highlights of the President’s Oral Sessions – the very final event of ADA, highlighting particularly notable late-breaking abstracts – and we will be watching the progress of this work very closely. Although this work is clearly in its earliest stages, REMD-477 is a perfect exemplification of a patient-friendly diabetes therapy that optimizes important outcomes beyond A1c – namely time-in-range and a vastly reduced injection burden.

Oral Presentations: New Insights into Prevention and Treatment of Hypoglycemia

Nasal Glucagon for the Treatment of Moderate-to-Severe Hypoglycemic Episodes in Real-World Settings in Adults with Type 1 Diabetes

Elizabeth Seaquist, MD (University of Minnesota, Minneapolis, MN)

Dr. Elizabeth Seaquist presented positive real-world data on Lilly’s phase 3 nasal glucagon, showing that 96% of patients experiencing hypoglycemia recovered within 30 minutes following treatment and that most of the caregivers were highly satisfied with the device. The study enrolled 129 adults with type 1 diabetes, and 69 of these participants experienced a total of 157 symptomatic moderate or severe hypoglycemia events (a blood glucose of approximately <60 mg/dl or requiring assistance) during the course of the study. For 151 of these episodes (96%), a 3 mg dose of nasally-delivered glucagon met its primary endpoint of “awakening or returning to normal status” within 30 minutes, as determined by a caregiver. For five of the remaining six events, caregivers noted recovery within 45 minutes, and in four of these instances, the patient’s blood glucose was ≥70 mg/dl 30 minutes after administering nasal glucagon. These are impressive results in a real-world setting, confirming what Locemia showed in phase 3 RCTs (Lilly acquired this pipeline product from Locemia in October 2015). A majority of caregivers, 70%, were able to deliver nasal glucagon to a patient experiencing hypoglycemia within 30 seconds, while 98% were able to do so in <2 minutes – what an exciting and much-needed improvement to the lengthy reconstitution process of existing glucagon options. Overall, 94% of caregivers were satisfied with nasal glucagon, including 56% giving it the highest “very satisfied” score. Dr. Seaquist emphasized that no calls to emergency services were made for any of the 157 hypoglycemia episodes, not even for 12 cases of severe hypoglycemia when patients were unconscious or experiencing convulsions or mental disorientation. Impressively, nasal glucagon met the study’s primary endpoint of recovery within 30 minutes in all 12 of these cases as well (experienced by seven participants), which supports the agent’s ability to rapidly raise dangerously low blood glucose in real-world settings. Though an FDA submission has taken longer than we expected since Lilly acquired the phase 3 product from Locemia (due to additional development work and establishing a manufacturing infrastructure), management shared in a separate interview with us that a filing is expected in 1H18, and the product will be submitted in other geographies shortly thereafter. The health and healtheconomic burden of hypoglycemia remains far too high, and we’re hopeful that advances like Lilly’s nasal glucagon will bring us leaps and bounds ahead in our ability to treat the complication. To that end, it’s extremely valuable to see real-world efficacy and feasibility data, since the immediate goal is to help patients/caregivers address hypoglycemia swiftly in everyday settings, avoiding an expensive hospital visit, emergency call, or need for a healthcare professional.

• During a separate call with Dr. Seaquist and Lilly’s nasal glucagon team, we heard anecdotal evidence on caregiver responses to this innovative product: “it just makes so much sense to them.” Certainly, this intuitive ease of use is crucial for a product like glucagon, used often in high-stress emergency situations. Once nasal glucagon is available, we’ll be fascinated to see how the ease-of-use and satisfaction compares to upcoming auto-injectors in development (Xeris and Zealand, among others). 
• According to Lilly management, the shelf life of this innovative product is anticipated to be comparable to current recombinant glucagon. We were happy to hear this, as it will be another pull for patients, providers, and payers. Cost is of course a big question with glucagon, and we so hope that this nasal glucagon is priced responsibly to maximize access to a superior, patient-friendly, cost-saving therapy. 
• Locemia presented equally positive simulated usability data at EASD 2015, which also highlighted the simplicity of nasal delivery.

Oral Presentations: Obesity Pathogenesis and Treatment – Insights from Mouse Models

PB-718, a Dual GLP-1/Glucagon Receptor Agonist Demonstrates Superior Weight Loss Effect and Ameliorates Nonalcoholic Steatohepatitis (NASH) in Animal Models

Michael Xu, MD (Pegbio, Suzhou, China)

Dr. Michael Xu presented a range of preclinical data on an investigational, PEGylated GLP-1/glucagon receptor dual agonist – Pegbio’s PB-718. In a mouse model of diabetes (n=6), both low and high doses of the agent were associated with superior weight loss and reduced fasting plasma glucose vs. twice-daily liraglutide. In mice with NASH (n=6), both doses led to more weight loss, a greater reduction in liver weight, and a greater lowering of liver weight/body weight ratio vs. placebo (p<0.0001 for all comparisons). Moreover, there was a dose-dependent reduction in NAS score for NASH severity (p<0.01 for lower dose vs. placebo; p<0.0001 for higher dose vs. placebo), which takes into account steatosis, liver inflammation, fibrosis, and other markers. Dr. Xu also reviewed findings from a preclinical investigation of Pegbio’s drug candidate in monkeys. Consistent with the data from rodent studies, PB-718 demonstrated dose-dependent and significant superiority vs. placebo in stimulating weight loss and improving NAS score. Dr. Xu explained that there are strong mechanistic underpinnings that support the utility of GLP-1/glucagon dual agonists for diabetes, obesity, and NASH. Oxynotomodulin, an endogenous dual agonist of GLP-1/glucagon, has been correlated with decreased food intake, enhanced glucose tolerance, and improved liver health. We’re certainly excited by GLP-1/glucagon dual agonists as a potential new therapy class (competitive landscape here), and we’re happy to see companies investing in these agents for diabetes as well as adjacent indications. NASH, in particular, is a therapeutic area of high unmet need with no FDA-approved medicines to-date, and we also see marked room for improvement in available tools for obesity management.

Questions and Answers

Q: Have you compared your agent with semaglutide (Novo Nordisk’s GLP-1 agonist candidate, in phase 2 for obesity and NASH)?

A: No we have not, but we will be eager to compare our compound to semaglutide in some study. Actually, we were approached by them and tried to figure out how to compare these compounds side-by-side. Of course, semaglutide has not yet been approved.

Oral Presentations: Central Nervous System Regulation of Metabolism

Diabetes Remission Induced by Central FGF1 Is Associated with Improved Beta-Cell Function

Jenny Brown, PhD Student (University of Washington, Seattle, WA)

Ms. Jenny Brown presented data from her work in Dr. Michael Schwartz’s lab on the role of FGF1 on glucose homeostasis regulated by the brain. Dr. Schwartz’s team published an article in Nature Medicine last May demonstrating that a single intracerebroventricular (ICV) injection of FGF1 resulted in sustained remission of type 2 diabetes in mouse and rat models. The beneficial effects of central FGF1 appeared to be related to insulin secretion, as the compound was not effective in rodent models of severe insulin deficiency. Ms. Brown aimed to build on this work by answering two questions: i) Does FGF1 increase insulin secretion in animals in remission? and ii) Does diabetes remission induced by FGF1 involve other mechanisms besides increased insulin secretion? A modified hyperglycemic clamp study in rats indicated that FGF1-induced diabetes remission was associated with increased basal insulin secretion but not with increased insulin secretion in response to a glucose infusion. However, increased basal insulin secretion does not appear to be the whole story, as a modified hyperinsulinemic clamp study in rats showed that vehicle-treated animals required higher plasma insulin levels to achieve the same plasma glucose as the FGF1-treated group. It is not yet clear what the additional glucose-lowering mechanisms might be, but Ms. Brown suggested that all of these findings support a revised model of glucose homeostasis that involves a central role for the brain. We’ve been very intrigued by the work from Dr. Schwartz lab on the role of the brain in both diabetes and in obesity – our interview with him last year was absolutely fascinating and we’ve been eagerly watching closely to see what other learnings his lab may produce.

Questions and Answers

Q: Did you see the same results in female rats?

A: We haven’t tested that yet but we plan to.

Q: We just learned in an earlier talk that the dorsal vagal complex could be manipulated with a high-fat diet. Could there be an additional effect related to modulation of that complex by FGF-1?

A: We’re looking at the specific nuclei where it’s acting now.

Q: What is the source of FGF-1? Is it naturally found in those areas? What is the difference between putting it in the brain vs. the periphery?

A: When it’s given peripherally, it’s given at multiple doses. That leads to reductions in body weight and food intake. The single brain injection induces acute reductions but they’re not sustained.

Q: Did they lose their overeating behavior? Were there any other behavioral changes after a week?

A: Body weight and food intake went back to the same level as the controls. The treated animals actually weighed slightly more at the end.

Oral Presentations: Targets and Pathways in Diabetic Kidney Disease

PBI-4050 Protects against Diabetic Nephropathy and Improves Pancreatic Function in High-Fat-Diet db/db Mouse Model

Lyne Gagnon, PhD (Prometic BioSciences, Laval, Quebec, Canada)

Dr. Lyne Gagnon discussed preclinical and phase 2 data for Prometic BioSciences’ anti-fibrotic drug candidate PBI-4050. This small molecule candidate  is an agonist of an undisclosed receptor with a protective role in fibrosis and an antagonist of a second undisclosed receptor with a deleterious role in fibrosis. Data from several preclinical models have demonstrated that the compound reduces fibrosis in the lungs, kidneys, heart, and liver and has positive effects on a wide range of metabolic parameters: reduced triglycerides, increased adiponectin, decreased hyperfiltration, downregulation of inflammatory markers, increased serum insulin, and reduced liver steatosis. Dr. Gagnon reviewed results presented at AHA last November from an open-label phase 2 trial of PBI-4050 in patients with type 2 diabetes. Results demonstrated a 0.75% A1c reduction after 12 weeks among patients with a baseline A1c ≥7.5% and a 0.9% reduction among patients with a baseline A1c ≥8%. The trial also found significant reductions in several biomarkers of kidney injury and improvements in a number of biomarkers of metabolic syndrome and fibrosis. Dr. Gagnon suggested that the drug’s ability to target multiple organs (kidneys, adipose tissue, liver, pancreas, muscle) could give it an edge over existing type 2 diabetes medications. We agree that the candidate’s widespread effects and anti-fibrotic activity make it an intriguing candidate but believe that in the current environment, it will need to demonstrate a beneficial effect on cardiovascular and/or renal outcomes in order to be truly competitive. The early-stage findings are certainly suggestive, though it’s unclear if the data shared thus far would be compelling enough to encourage the massive investment of a large-scale phase 3 program in type 2 diabetes, including a CVOT.

Questions and Answers

Q: Was the gene expression data from the whole kidney or the cortex?

A: This data was from the cortex.

Q: What is the specific mechanism of action?

A: The drug acts on two receptors. I can’t say which specific ones for patent reasons.

Q: You mentioned that microparticles are reduced. What are microparticles and why are they important?

A: There was some indication that there was a reduction of microparticles from podocytes. This suggests that the compound is protecting podocytes.

Q: Do you think the anti-fibrotic effects are mainly due to FGF?

A: No, there’s regulation of many cytokines, growth factors, etc. It’s more than just FGF.

Q: Are there side effects?

A: The compound appears very safe and well tolerated. There were very few side effects. There was diarrhea in two patients. We have two more posters focused on side effects and other results, including a small but significant reduction in BMI.

Q: Was there any negative effect on wound healing or other processes that require fibrosis?

A: Good question. We saw no effect on wound healing.

Posters

Dasiglucagon, a Novel Soluble Glucagon Analog, Successfully Restores Blood Glucose Levels after Hypoglycemia in People with Type 1 Diabetes Mellitus (T1DM) (389-P)

T Heise, B Bysted, U Mouritzen, U Hovelmann, D Lamers, and D Moller

Zealand presented a poster detailing phase 2 results from a PK/PD study of its liquid-stable glucagon analog dasiglucagon. The trial compared four doses of dasiglucagon (0.1 mg, 0.3 mg, 0.6 mg, and 1.0 mg) to native glucagon (Novo Nordisk’s GlucaGen; 0.5 mg and 1.0 mg) in participants with type 1 diabetes (n=58), demonstrating that dasiglucagon, like native glucagon, was able to rapidly and effectively increase blood glucose concentration following a controlled, insulin-induced hypoglycemia event in which blood glucose fell to 55 mg/dl. On the pharmacodynamic front, the three highest dasiglucagon doses (0.3 mg, 0.6 mg, and 1.0 mg) each took a median of six minutes to raise plasma glucose levels to above 70 mg/dl, versus 6 and 7 minutes for the 0.5 mg and 1.0 mg doses of native glucagon, respectively (and 10 minutes for the 0.1 mg dasiglucagon dose). Dasiglucagon furthermore showed comparable performance to native glucagon in terms of the average time required to increase plasma glucose levels by 20 mg/dl; the four dasiglucagon doses (0.1 mg, 0.3 mg, 0.6 mg, and 1.0 mg) respectively took a median of 14, 10, 9, and 9 minutes to achieve this level of plasma glucose reduction, versus 10 minutes for both the 0.5 mg and 1.0 mg native glucagon doses. Notably, the increase in plasma glucose was longer-lasting and more pronounced with dasiglucagon: total plasma glucose excursions (as measured by area under the effect curve [AUE]) were significantly higher with 0.3 mg dasiglucagon versus 0.5 mg native glucagon (p<0.0001) and for both 0.6 mg (p=0.0043) and 1 mg (p<0.0001) dasiglucagon versus 1.0 mg native glucagon. This larger glucose excursion profile promisingly suggests that dasiglucagon may be superior to native glucagon at preventing recurrent hypoglycemia. On the pharmacokinetic front, dasiglucagon reached maximum exposure significantly later than native glucagon (~35 minutes; p<0.01), but demonstrated a significantly higher total exposure for all dose comparisons (p<0.001). In a separate conversation with Zealand, the company indicated that this could be suggestive of higher viability for dasiglucagon over native glucagon, meaning that dasiglucagon could achieve the same the same glucose increasing efficacy at lower doses – but of course this would need to be verified in future studies. Importantly, dasiglucagon was well-tolerated with a similar safety profile as native glucagon. For both dasiglucagon and native glucagon, the most commonly reported adverse events were nausea and vomiting (40 events with dasiglucagon, 35 events with native glucagon) and mild injection site reactions which disappeared within 30 minutes post-dosing (7 events with dasiglucagon, 5 events with native glucagon).

• Following the release of these topline results in 3Q16, Zealand commented in its 4Q16 earnings update that the FDA is expected to provide guidance of dasiglucagon’s development in 1Q17. The candidate is currently in phase 2 development both as a single-dose rescue pen (phase 3 to begin as soon as 3Q17) and as a multi-dose component of a dual hormone artificial pancreas system. We are very pleased to see this progress toward a more patient-friendly and feasible alternative to the current very complex, error-prone native glucagon kits – a longstanding area for improvement in diabetes care. For more on the soluble glucagon arena more broadly, check out our soluble glucagon competitive landscape.

Mini-Dose Glucagon as a Novel Approach to Prevent Exercise-Induced Hypoglycemia in Type 1 Diabetes (67-LB)

M Rickels, S Dubose, H Wolpert, E Toschi, R Beck, M Cummins, BJ Newswanger, and MC Riddell

This phase 2 study compared Xeris’ G-Pen Mini glucagon vs. basal insulin reduction vs. glucose tabs as a way to avoid exercise-induced hypoglycemia, a persistent problem since the natural glucagon response is impaired in people with type 1 diabetes. Each trial participant (n=15) went through four conditions in a randomized crossover design: (i) control, (ii) 50% basal rate reduction five minutes prior to the start of exercise, (iii) oral glucose tabs (20 grams five minutes before start, and another 20 grams 30 minutes after start), and (iv) Xeris’ mini-dose glucagon injected subcutaneously into the abdomen five minutes prior to the start of exercise. The G-pen injection maintained plasma glucose levels between 125-175 mg/dl throughout the duration of exercise (45 minutes) and for 45 minutes after, while glucose tabs elevated blood sugar >225 mg/dl 45 minutes-post exercise. Basal insulin reduction was significantly less effective in avoiding hypoglycemia (p<0.001 vs. G-Pen), as mean plasma glucose dropped to ~75 mg/dl by the end of exercise and stayed low for 45 minutes after, which parallels almost exactly what happened on average in the control condition. In total, six people experienced hypoglycemia (defined by blood sugar <70 mg/dl) in the control condition, five in the basal rate reduction condition, and none in the mini-dose glucagon or oral tabs conditions. On the opposite end, five individuals experienced hyperglycemia (defined by blood sugar >250 mg/dl) in the oral tabs condition vs. only one in the mini-dose glucagon condition and none in the control or basal rate reduction conditions. These results show promising early efficacy for Xeris’ G-Pen Mini as a solution for exercise-induced hypoglycemia in type 1 diabetes – compared to control, basal insulin reduction, and oral glucose tabs, this mini-dose of glucagon minimized both hypoglycemia and hyperglycemia during and immediately after exercise. This study is particularly important since it also  shows how much more effective a small dose of glucagon is if given just before exercise, rather than waiting until hypoglycemia develops during exercise, the latter of which is repeatedly observed in duel hormone studies using glucagon in artificial pancreas  studies. The poster concludes that this phase 2 data supports a larger, longer-term study of Xeris’ G-Pen Mini, which we’d love to see. Xeris currently has one of the most advanced clinical programs for glucagon, and we’ll be watching eagerly for updates. See our glucagon competitive landscape for more information.

Ultra-Rapid Biochaperone Lispro Improves Post-Prandial Glucose Excursions Versus Insulin Lispro in a 14-day Treatment Study in Subjects with Type 1 Diabetes (964-P)

G Andersen, G Meiffren, D Lamers, A Ranson, B Alluis, M Gaudier, O Soula, T Heise, and S Bruce

Adocia’s ultra-rapid BioChaperone Lispro (BCLIS) demonstrated an accelerated absorption profile and significant reductions in postprandial glucose excursions compared with insulin lispro (Lilly’s Humalog) in people with type 1 diabetes. The randomized, monocentric, double-blind, comparator-controlled 14-day phase 1 crossover trial enrolled 36 participants (mean age 45 ± 12 years) with type 1 diabetes. Patients were randomized to receive bolus doses of either BCLIS or insulin lispro for 14 days. While in the inpatient setting for days 1-3 and 14 of the study, patients received the insulin they had been assigned to 15 minutes before, immediately before, or 15 minutes after an individualized mixed-meal, with blood samples and lispro concentrations subsequently measured. Patients continued the insulin regimens to which they had been randomized in the outpatient setting on days 4-13, and additionally self-measured plasma glucose (SMPG) levels four times daily.  BCLIS insulin had a “faster-in/faster-out” profile than insulin lispro. BCLIS dosing additionally resulted in significantly lower post-meal glycemic excursions as compared to insulin lispro  if the insulin was dosed immediately before the meal’s start or 15 minutes thereafter. Notably, postprandial glycemic excursion profiles were similar between BCLIS injected fifteen minutes after a meal’s start and insulin lispro injected immediately before a meal’s start. Mean outpatient SMPG values didn’t differ significantly BCLIS and insulin lispro. Safety profiles were also similar between the treatment groups. 

Ultra-Rapid Biochaperone Lispro Improves Postprandial Blood Glucose Control versus Humalog in a 14-day Treatment Study in Subjects with Type 2 Diabetes (994-P)

T Heise, G Meiffren, D Lamers, B Kronshage, A Ranson, B Alluis, M Gaudier, E Anastassiadis, O Soula, and S Bruce

Adocia’s ultra-rapid BioChaperone lispro (BCLIS) demonstrated an accelerated absorption profile and significant reductions in postprandial glucose control versus insulin lispro (Lilly’s Humalog) in people with type 2 diabetes. The randomized, monocentric, double-blind, comparator controlled 14-day crossover phase 1 trial enrolled 51 participants (mean age 62 ± 9 years) with type 2 diabetes. Participants were randomized to receive either individualized BCLIS or insulin lispro bolus doses with meals. On inpatient days 1-2 and 13-14, patients received the insulin to which they had been randomized with an individualized mixed-meal, after which blood samples and lispro concentrations were assessed. In the outpatient setting on days 3-12, patients continued their assigned insulin regimens and measured their plasma glucose (SMPG) levels.  BCLIS insulin had a “faster-in/faster-out” profile than insulin lispro. BCLIS additionally resulted in significant reductions in post-prandial glucose exposure for up to three hours after dosing as compared with insulin lispro.  Differences in glycemic excursions between treatments were most pronounced on days 13-14. Mean outpatient SMPG values didn’t differ significantly between BCLIS and insulin lispro, but notably, similar values were achieved with 10% lower BCLIS doses. Treatment with BCLIS was safe and well tolerated. 

SORELLA-1: Similar One-Year Efficacy and Safety in People with T1DM Using SAR342434 or Insulin Lispro in Combination with Insulin Glargine (Gla-100) (1003-P)

S Garg, K Wernicke-Panten, M Rojeski, S Pierre, and K Jedynasty

This poster featured one year data from the phase 3 SORELLA 1 study, demonstrating the non-inferiority of Sanofi’s SAR34233, a rapid-acting follow-on biologic to insulin lispro, to the originator product (Lilly’s Humalog) in people with type 1 diabetes, reinforcing the 26-week findings presented at ADA 2016. Developed as a rapid acting follow-on product to Humalog, SAR has an identical amino acid sequence to that of insulin lispro and a previous clamp study determined that SAR was similar in pharmacokinetic exposure and pharmacodynamics activity to insulin lispro. In the study, 507 people with type 1 diabetes were randomized to receive either a multiple daily injection regimen of SAR or insulin lispro in addition to once-daily insulin glargine. At 52 weeks, the SAR and insulin lispro groups exhibited a LS mean difference in A1c of 0.06% (95% CI: -0.084% to 0.197%), solidly indicating non-inferiority between the two drugs. In addition, both groups showed similar post-prandial glucose excursions and insulin dosages. Almost all patients reported at least one episode of hypoglycemia, but with similar incidence between the SAR and insulin lispro groups for all categories of hypoglycemia: severe (13.5% vs. 13.4%), documented symptomatic <70 mg/dl (87.3% vs. 89.8%), and asymptomatic <70 mg/dl (97.2% vs. 97.6%).Furthermore, in both SAR- and insulin lispro- treated patients, anti-insulin lispro antibody incidence levels were similar (62.5% vs. 63.1% respectively). Each treatment group had two patients who discontinued treatment due to a treatment-emergent adverse event: 54.4% of SAR-treated and 55.5% of insulin lispro-treated participants reported any adverse event. Thus, the study’s findings concluded that SAR was just as effective and well-tolerated as insulin lispro in people with type 1 diabetes.

Similar Glucose Control, Postprandial Glucose Excursions, and Safety in People with T2DM Using SAR342434 or Insulin Lispro in Combination with Insulin Glargine (Gla-100): SORELLA 2 Study (1004-P)

KM Derwahl, T Bailey, K Wernicke-Panten, L Ping, and S Pierre

This poster featured initial phase 3 data from the SORELLA 2 study, demonstrating the non-inferiority of Sanofi’s SAR34233, a rapid-acting follow-on biologic to insulin lispro, to the originator product (Lilly’s Humalog) in people with type 2 diabetes. Developed as a rapid acting follow-on product to Humalog, SAR has an identical amino acid sequence to that of insulin lispro and a previous clamp study determined that SAR was similar in pharmacokinetic exposure and pharmacodynamics activity to insulin lispro. In the study, 505 people with type 2 diabetes (mean age 62 years; mean BMI 32 kg/m3; mean A1c 8%) were randomized to receive either a multiple daily injection regimen of SAR or insulin lispro in addition to once-daily insulin glargine. At 26 weeks, the SAR and insulin lispro groups exhibited a LS mean difference in A1c of -0.07% (95% CI: -0.215% to 0.067%), solidly indicating non-inferiority between the two drugs. In addition, both groups showed similar post-prandial glucose excursions and insulin dosages. Almost all patients reported at least one episode of hypoglycemia, but with similar incidence between the SAR and insulin lispro groups for all prespecified categories of hypoglycemia: severe (2.4% vs. 1.6%), documented symptomatic <70 mg/dl (60.1% vs. 66.3%), and asymptomatic <70 mg/dl (35.2% vs. 37.3%).Furthermore, in both SAR- and insulin lispro- treated patients, anti-insulin lispro antibody incidence levels were similar (38.4% vs. 36.7% respectively). Each treatment group had two patients who discontinued treatment due to a treatment-emergent adverse event: 46.6% of SAR-treated and 42.9% of insulin lispro-treated participants reported any adverse event. There was one death in the SAR arm and two deaths in the insulin lispro arm, but these were unrelated to the study drug. Thus, the study’s findings concluded that SAR was just as effective and well-tolerated as insulin lispro in people with type 2 diabetes.

Efficacy and Safety of Mini-Dose Glucagon for Treatment of Nonsevere Hypoglycemia in Adults with Type 1 Diabetes (1068-P)

MW Haymond, S Dubose, MR Rickels, H Wolpert, VN Shah, JL Sherr, RS Weinstock, S Agarwal, AS Verdejo, MJ Cummins, B Newswanger, and RW Beck

Xeris’ G-Pen Mini was investigated in 17 adults with type 1 diabetes as a treatment for nonsevere hypoglycemia. In a randomized crossover design, participants spent three weeks with mini-dose glucagon and three weeks with oral glucose tabs to treat any cases of mild hypoglycemia. The primary endpoint of “success” was defined as blood glucose ≥50 mg/dl 15 minutes following treatment and blood glucose ≥70 mg/dl 30 minutes following treatment – 94% of patients in the mini-dose glucagon arm achieved success vs. 95% of patients in the glucose tabs arm. BGM and CGM data showed a similar profile for the G-Pen Mini vs. oral glucose tabs. In the first hour post-hypoglycemic event, people in the glucagon group spent 62% of time-in-range vs. 67% for people in the glucose tabs group (p=0.86). In the first two hours post-hypoglycemic event, participants in both groups spent a mean 79% of time-in-range (p=0.49). Time <70 mg/dl was a mean 35% for the glucagon group one hour post-hypoglycemia vs. 33% for the glucose tabs group (p=0.95). Two hours post-hypoglycemia, these values were 20% and 19%, respectively (p=0.63). The non-significant p-values indicate the G-Pen Mini’s non-inferiority vs. oral glucose tabs as a treatment for mild hypoglycemia, but the poster points out other distinct advantages to mini-dose glucagon: Namely, carbohydrates as a solution to nonsevere hypoglycemia lead to excess caloric intake and excess hyperglycemia, all of which could be avoided with Xeris’ G-Pen Mini. After six weeks of the study, participants were asked to choose between the two treatment options for an additional three weeks – ~50% opted to continue mini-dose glucagon. Injection discomfort and nausea were the primary reported adverse events associated with the G-Pen Mini, affecting 15 and three participants, respectively. Overall, these results support continued investigation of Xeris’ product for mild-to-moderate hypoglycemia, and we look forward to future data readouts. Xeris is an industry leader right now in the glucagon competitive landscape, and we’re very happy to see forward progress on the company’s various glucagon candidates.

A Phase 1b, Randomized, Placebo-Controlled, Multiple-Dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of AMG 876, a Novel Fc-FGF-21 Fusion Protein, in Subjects with Type 2 Diabetes Mellitus (1069-P)

L Abuqayyas, M Tracy, S Smith, A Anderson, and A Kaufman

A phase 1b study of Amgen’s FGF21 candidate AMG 876 found the agent to be safe and well-tolerated at various doses (7 mg, 21 mg, 70 mg, or 140 mg either once- or twice-weekly). In total, there were 43 treatment-emergent adverse events among 52 patients with type 2 diabetes randomized to AMG 876 (83%) vs. 12 such events among 17 patients randomized to placebo (71%). There were no serious adverse events or fatalities throughout the trial, although only one participant in the placebo arm discontinued treatment vs. five participants in the FGF21 arm – four of these were in the highest-dose group, reporting (i) vomiting, (ii) diarrhea, (iii) tremors/nausea, and (iv) tremors. Efficacy was investigated as a secondary endpoint in this phase 1b trial. The poster reports significant reductions in fasting and postprandial glucose with AMG 876 vs. placebo. Amgen’s candidate was also associated with a clinically-meaningful decrease in triglyceride levels and an increase in HDL cholesterol vs. placebo. FGF21 analogs seem to be getting more attention in the diabetes/obesity fields of-late, with new pipeline candidates from Amgen (for type 2 diabetes), Novo Nordisk (for obesity), BMS (for NASH), and Roche (indication not yet announced). There’s a lot of interest brewing in this potential new therapy class, but we also recognize that all of these candidates remain extremely early-stage and will have a long road ahead through clinical development before possibly reaching the commercial market. Notably, both Lilly and Pfizer discontinued their FGF21 candidates for type 2 diabetes following lackluster glucose-lowering results from phase 2 trials.

Results of a Phase 2 Study of the Oxyntomodulin (OXM) Analogue LY2944876 in Patients with Type 2 Diabetes (T2DM) (1070-P)

M Sheetz, R Bray, LS Tham, C Jones, J Kinsella, and R Violante-Ortiz

Lilly presented full phase 2 results for its PEGylated GLP-1/glucagon dual agonist, oxyntomodulin analog LY2944876 in patients with type 2 diabetes. In this 24-week trial, 420 patients were randomized to once-weekly injections of one of four doses of LY2944876 (10 mg, 15 mg, 30 mg, or 50 mg), exenatide once-weekly (AZ’s GLP-1 agonist Bydureon), or placebo. At both week 12 and week 24, LY2944876 demonstrated superiority to placebo and non-inferiority to exenatide for the primary endpoint of A1c reduction. A1c reductions were largely dose-dependent for LY2944876 and ranged from ~0.8% to ~1.4%. At the highest 50 mg dose, LY2944876 produced statistically superior weight reductions compared to exenatide and placebo (p=0.044 and p=0.007, respectively). However, the finding did not achieve the predefined criterion for superior weight loss (a posterior probability [PP] of ≥60% by Bayesian analysis with a margin of 1.5 kg – LY2944876 only achieved a PP of 29.4%). Lilly also shared several additional results of interest. At week 24, significantly more patients in the 50 mg dose group had achieved a weight loss of ≥5% body weight (35.5%) than in the placebo (11.8%, p=0.004) or exenatide (18.3%, p=0.025) groups. That said, at week 24, the proportion of participants achieving A1c ≤7% or ≤6.5% in the 50 mg dose group was comparable to that of the exenatide arm. Lilly also reported that fasting glucagon levels were reduced by approximately 40% in the 50 mg group, compared to a ~12% reduction in the exenatide group. There was no significant chance in blood pressure between any of the groups. Heart rate increased in the two highest dose groups for the dual agonist, but the increase was less than the increase observed with exenatide (p<0.05). Adverse events associated with the dual agonist were similar to what might be expected with a selective GLP-1 agonist, largely consisting of GI events.

• Lilly previously partnered with Transition Therapeutics on the development of this candidate, before declining to advance the candidate into phase 3, despite its status as a potential first-to-market GLP-1/glucagon dual agonist. Transition Therapeutics – and this candidate – have since been acquired by OPKO Health, which is investigating a potential obesity indication for this drug, rather than a type 2 diabetes indication. We previously learned that the topline results met the trial’s primary endpoint and demonstrated non-inferiority to exenatide in terms of A1c and superiority in terms of body weight. Full results in hand, however, it’s clear that the weight loss superiority did not meet the predefined criteria that Lilly was looking for. Given its robust portfolio of newly-launched diabetes drugs and early-stage pipeline efforts, Lilly understandably has a very high internal threshold for continued clinical development of its candidates – and particularly for advance into phase 3. Lilly also appears to somewhat favor its internally-developed diabetes candidates to licensed molecules (with the notable exception of the very successful BI alliance, and its acquisition of Locemia’s nasal glucagon). Indeed, Lilly’s phase 1 pipeline includes an internally-developed, once-weekly GLP-1/glucagon dual agonist for type 2 diabetes and NASH, a candidate that was added after the decision not to pursue the Transition Therapeutics partnership further. See our GLP-1/glucagon dual agonist competitive landscape an overview of the robust industry investment in this area.

The Effect of NNC0090-2746, a Dual GIP/GLP-1 Receptor Agonist (RA), on Glycemic Control, Plasma Cholesterol, and Body Weight in Subjects with Type 2 Diabetes: A Phase 2a Randomized Clinical Trial (1071-P)

JP Frias, EJ Bastyr, L Vignati, M Tschöp, C Schmitt, K Owen, RH Christensen, and R DiMarchi

This poster featured phase 2a data deonstrating significant improvements in glycemic control, body weight, and cholesterol with Novo Nordisk’s GIP/GLP-1 receptor agonist NNC0090-2746 compared to placebo after 12 weeks in people with type 2 diabetes. These promising results come on the heels of a separate poster presented at ADA overviewing phase 1 evidence that the candidate is well-tolerated in doses of up to 2 mg in people with type 2 diabetes and can produce meaningful reductings in fasting, post-prandial, and 24 hour profile plasma glucose, as well as A1c reductions of up to 0.67%, after two weeks (1095-P). In this phase 2a study, 108 people with type 2 diabetes (average age 55 years, average A1c 8.3%, average diabetes duration 8 years) were randomized to receive NNC009-2746, placebo, or Novo Nordisk’s GLP-1 agonist Victoza (liraglutide). The Victoza arm was open-label, and this analysis only statistically compares the double-blind NNC009-2746 and placebo arms. After 12 weeks, participants taking the GIP/GLP-1 agonist showed significant improvement in the primary endpoints of A1c reduction: relative to placebo, A1c was reduced 0.63% in the treatment group (95% CI: -0.93 to -0.33; p<0.0001). The GIP/GLP-1 agonist also produced significant reductions in mean 7-point SMPG (-31.7 mg/dl, p<0.0001) and FPG (-38.2 mg/dl, p<0.0001). As for the key secondary endpoint of body weight, NNC009-2746 produced significant weight loss relative to placebo at 8 weeks (-1.8% treatment difference, p=0.0141) but the trend lost significance at week 12 (-1.6%, p<0.05). However, significant improvements were maintained throughout the entire study in various adipose biomarkers and lipid parameters, including total cholesterol (treatment difference -0.92  mg/dl, p=0.02) and plasma leptin levels (treatment difference -0.78 mg/dl, p=0.018). Interestingly, a post-hoc analysis revealed a significant interaction between baseline A1c and body weight reduction such that participants with a baseline A1c  below 8.5% lost significantly more weight with the GIP/GLP-1 agonist relative to placebo than those with an A1c above 8.5% (p for interaction = 0.041), suggesting that the maximum benefit of NNC0090-2746 with respect to weight loss is obtained by people with already near-target glycemic control. As for adverse events, the treatment group experienced more adverse events than the placebo group (65% vs. 42%), driven by a higher proportion of gastrointestinal adverse events (35% vs. 17%) as expected with agents in the GLP-1 agonist family. Together, these results support the safety and efficacy of NNC0090-2746 for impoving glycemic control and reducing body weight (especially for those already with good glycemic control).

Safety, Pharmacokinetics, and Pharmacodynamics of Multiple Ascending Doses of the Novel Dual GIP/GLP-1 Agonist RG7697 in Patients with Type 2 Diabetes Mellitus (1095-P)

C Schmitt, A Portron, S Jadidi, N Sarkar, and R Dimarchi

This poster shared phase 1 data on Roche’s now-discontinued GLP-1/GIP dual agonist, RG7697.  In the multiple ascending dose study, patients with type 2 diabetes (n=56) on a stable dose of metformin for at least two months were randomized to receive either once-daily subcutaneous injections of RG7697 (doses ranging from 0.25-2.5 mg) or placebo for two weeks. Daily injections of RG7697 were generally well-tolerated, although the most frequent adverse events included hypoglycemia, diarrhea, nausea, headache, and decreased appetite. One patient withdrew from the study due to adverse events of hypokalemia, dehydration, and acute renal failure. Reversible treatment-related increases in heart rate, lipase, and amylase were recorded. PK steady state was achieved after seven days, and PD data showed a dose-dependent glucose-lowering effect vs. placebo, with mean absolute A1c reductions between 0.41% and 0.67% after 16 days. Postprandial glucose concentrations were reduced 37% from baseline and postprandial insulin concentrations were reduced at doses of the agent ≥1.1 mg, suggesting an increase in insulin sensitivity. That said, efficacy was a secondary endpoint in this trial, and ultimately a combination of these safety and efficacy findings led to Roche’s decision to discontinue RG7697 from its pipeline. GLP-1/GIP dual agonists present an exciting advancement in diabetes therapy, although the most advanced candidates on this competitive landscape remain very early-stage, in phase 1. We hope that these results, even though the candidate was discontinued, help inform other existing clinical development programs for GLP-1/GIP dual agonists.

Potent Body Weight Loss and Efficacy in a NASH Animal Model by a Novel Long-Acting GLP-1/Glucagon/GIP Tri-agonist (HM15211) (1139-P)

IY Choi, JS Lee, JK Kim, YJ Park, S Jung, YH Kim, and SC Kwon

This poster demonstrates preliminary evidence for the safety and efficacy of Hamni’s novel long-acting GLP-1/glucagon/GIP triple agonist HM15211 in rodent models of obesity and NASH. In rodents with diet-induced obesity, the triple agonist produced 35% body weight loss over four weeks, versus 19% weight loss with the GLP-1 agonist liraglutide (Novo Nordisk’s Victoza; p<0.001). The mechanism underlying this may be energy expenditure; despite similar food intake, animals treated with the triple agonist showed an energy expenditure of nearly 14 kcal/hour, versus only 13 kcal/hour for liraglutide and 12 kcal/hour with placebo (p<0.001). The efficacy of the GLP-1/glucagon/GIP triple agonist extends beyond obesity to NASH, demonstrating significant improvements over both liraglutide and placebo in measures of NASH prognosis, including hepatic triglycerides, hepatic thiobarbituric acid, lobular inflammation, and overall NAFLD Activity Score (NAS). Based on these promising results,  we expect the candidate to advance to in-human studies and we very much look forward to the phase 1 data.

Low Weekly Doses of IONIS-GCGRRX, a Second-Generation Antisense Glucagon Receptor Antagonist, Caused Significant Improvements in Glycemic Control in T2DM Patients on Stable Metformin Therapy (1158-P)

E Morgan, L Tai, SB Jung, R Geary, and S Bhanot

Ionis presented results from its phase 2b dose optimization study of glucagon receptor antagonist IONIS-GCGRRx on a poster (topline data was released in early January 2017). The 75 mg dose of the agent (n=21 type 2 diabetes patients on stable metformin therapy at baseline) was associated with a 1.6% A1c decline vs. a 0.2% mean A1c drop for participants (n=23) randomized to placebo (p<0.001). The 50 mg dose (n=20) was associated with a mean 0.9% A1c reduction (p<0.05 vs. placebo). Moreover, 67% of people in the 75 mg arm achieved A1c-lowering ≥1% vs. 9% of people in the placebo arm (p<0.001) and 45% of people in the 50 mg arm (p<0.01 vs. placebo). And, 38% of the 75 mg group achieved target A1c <7% (from a baseline 8.8%) vs. 9% of the placebo group (p<0.05). GLP-1 levels were increased in a dose-dependent fashion with IONIS-GCGRRx, while participants on placebo experienced a mean decline in GLP-1. While all of this efficacy data points to the superiority of the 75 mg dose, the poster also reports a 1.2x increase in ALT liver enzymes in this treatment arm vs. a mean decrease in the 50 mg arm. There were three confirmed cases of ALT levels increasing more than 3x in the 75 mg group, and none in the 50 mg group. The poster concludes that IONIS-GCGRRx could be titrated on an individual basis between 50-75 mg, since there was no statistically significant correlation between A1c-lowering and rise in ALT liver enzymes. On the whole, these results support continued clinical development for Ionis’ glucagon receptor antagonist candidate, possibly in combination with different oral type 2 diabetes therapies (such as SGLT-2 inhibitors).

• IONIS-GCGRRx is a potential first-in-class glucagon receptor antagonist, ahead of Ligand’s phase 2 candidate. While we’re excited to note clinical progress, we’re also aware of safety issues related to glucagon receptor antagonists, which led to the discontinuation of Lilly’s and Pfizer’s in-class candidates in 2Q15 and 4Q16, respectively. Pfizer recently added a glucagon receptor blocker to its phase 1 pipeline, which hints at the company’s continued confidence in this therapeutic target despite underwhelming results from its earlier phase 2 candidate.

Symposium: ADA Pathway to Stop Diabetes

Daniel Ceradini, MD (NYU Langone Medical Center, New York, NY); Joshua Thaler, MD (University of Washington, Seattle, WA); Praveen Sethupathy, MD (Cornell University, Ithaca, NY); Kathleen Page, MD (USC, Los Angeles, CA); Phillip White, MD (Duke University, Durham, NC)

As always, the ADA Pathway to Stop Diabetes symposium offered an inspiring glimpse at the future of diabetes management. We were particularly excited to hear from Dr. Zhen Gu (University of North Carolina, Chapel Hill, NC) on the variety of smart insulin delivery approaches his lab is researching. Echoing his talk at the JDRF Mission Summit in January, Dr. Gu discussed the merits of hypoxia-sensitive vs. pH-sensitive delivery systems and his early forays into the possibility of using red blood cells for smart insulin delivery. In his view, the main challenges facing the smart insulin field today are (i) achieving a fast response comparable to normal beta cell activity; (ii) avoiding hypoglycemia; (iii) achieving ease of administration; and (iv) ensuring biocompatibility. Other highlights from the symposium included:

• Dr. Daniel Ceradini (NYU Langone Medical Center, New York, NY) presented data showing that that siRNA-mediated Keap1 knockdown resulted in significantly accelerated diabetic wound closure in a humanized mouse model. The approach reduced wound burden by 60% and could potentially allow for improvements in quality of life and significant reductions in healthcare costs. We were very excited to see this research given this is an enormously expensive complication and one that is addressable.
• Dr. Joshua Thaler (University of Washington, Seattle, WA) discussed his research on how astrocyte and microglial inflammatory signaling promotes obesity susceptibility in high fat diet-fed mice.
• Dr. Praveen Sethupathy (Cornell University, Ithaca, NY) discussed recent findings demonstrating that a high-fat diet alters small intestinal morphology and physiology. His lab found that 20 weeks on this diet led to a significant increase in epithelial proliferation and a disproportionate allocation of stem cells and progenitors. In a promising proof of concept in fruit flies, he found that overexpression of a particular mRNA in stem cell compartments can almost completely suppress this proliferative response.
• Dr. Kathleen Page (USC, Los Angeles, CA) summarized recent findings implicating central adiposity in childhood as an early indicator of intrauterine exposure to gestational diabetes and maternal adiposity. We find the subject of epigenetics extremely interesting and hope to see more on this as an approach to reducing obesity longer-term.
• Dr. Phillip White (Duke Molecular Physiology Institute, Durham, NC) presented findings demonstrating that inhibition of the enzyme BDK improves glucose tolerance and lowers hepatic triglyceride content. BDK is an enzyme that regulates branched-chain amino acid metabolism along with PPM1K; its beneficial effects appear to be exerted through regulation of ATP-citrate lyase.

Responsive Vesicles Integrated with Transcutaneous Patches for Glucose-Mediated Insulin Delivery

Zhen Gu, PhD (University of North Carolina, Chapel Hill, NC)

Echoing his talk at the JDRF Mission Summit in January, Dr. Zhen Gu discussed several approaches to glucose-responsive insulin delivery that his iMedication lab is researching. Two projects – the microgel and nano-network approaches – use the enzyme glucose oxidase to convert glucose to gluconic acid and create an acidic environment that activates the release of insulin. While these approaches have shown some positive effects in preclinical models, Dr. Gu explained that response speed has been a challenge, as the body’s buffering ability makes it difficult to immediately generate an acidic environment. Therefore, the lab is also exploring a hypoxia-sensitive insulin patch that releases insulin when oxygen levels fall (both glucose and oxygen are consumed in the glucose oxidase reaction). Finally, Dr. Gu mentioned his lab’s preliminary efforts to use red blood cells for smart insulin delivery: the cells are coated with modified insulin that detaches in response to high glucose. In addition to speed, other key challenges that Dr. Gu cited include the risk of hypoglycemia, ease of administration, and biocompatibility.

Symposium: ADA Diabetes Symposium – Emerging Therapeutic Targets and Mechanisms of Action

Single-Molecule Combinatorial Therapeutics for Obesity and Diabetes

Matthias Tschöp, MD (Helmholtz Diabetes Center, Munich, Germany)

Dr. Matthias Tschöp offered an intriguing vision of a future in which patients with metabolic dysfunction could receive personalized treatment with dual or triple agonists that target their specific metabolic defects. He explained that a truly effective treatment for obesity probably needs to target the brain and that modulating endogenous gut-brain communication pathways is likely safer than directly altering neurotransmission. He reviewed published data showing beneficial effects of GLP-1/glucagon dual agonists and a GIP/GLP-1/glucagon triagonist on several metabolic parameters. He acknowledged that it is counterintuitive to use a glucagon agonist to reduce blood glucose and body weight but stressed that his lab has done a significant amount of mechanistic research to demonstrate that glucagon receptor agonism does have those effects in this case. The group’s current working hypothesis for that aspect of the triagonist’s mechanism is that the molecule leads to increased energy expenditure in adipose tissue by acting through FGF21 and adiponectin. Dr. Tschöp also reviewed data (presented as poster 1071-P) demonstrating significant and sustained improvements in glycemic control and body weight with GLP-1/GIP dual agonist NNC0090 in patients with type 2 diabetes. The study also found some reduction in total cholesterol and leptin, and the overall results suggest that the maximal weight benefit of this therapy occurs in patients with lower baseline A1c. Dr. Tschöp closed by briefly mentioning several other multi-agonist compounds his lab is working on, including GLP-1/estrogen, GLP-1/dexamethasone, glucagon/T3, and GLP-1/PPAR alpha dual agonists.

Questions and Answers

Q: It seems like you’ve hit a bunch of home runs by putting two or three things together. What doesn’t work?

A: This is always a bit misleading. Of course we’ve tried hundreds of things that don’t work. Most of my hypotheses were wrong and there’s lots of trial and error.

Q: At the end you mentioned interactions between estrogen and some other agents. Is there any data in rodent, primate, or human studies to suggest differential responses by sex?

A: We have been asked to perform those studies for the revision of our paper. GLP-1/estrogen works comparably in male and female rodents. The protection of the islet, which is quite striking, will probably be more prominent in rodents than humans.

Q: Does the target cell need to have all three receptors for the triagonist to work?

A: The simple answer is no. It is sufficient that the target cell has one receptor. The molecule can only bind one receptor at a time. We’ve dialed the affinity into the molecule so that if you give 100 molecules, 30 will bind to one receptor, 40 to another, etc. There’s no simultaneous binding to the best of our knowledge.

Q: If the agonist can bind to separate the receptors, as it comes off one could it get picked up by another on the same cell? Could there be a kinetic effect of the cell having multiple receptors?

A: I’m not sure but there’s no data indicating that.

Q: You talked about targeting the brain but your data didn’t relate to that. Have you done any ICV injection studies?

A: I didn’t include some of that data at the end for the sake of time. We haven’t done ICV injections but that’s currently going on. It’ll be more important to find out how much of our compounds is crossing the blood-brain barrier. My hunch is it’s not that much but that they are acting on the brain. When you knock out the brain GLP-1 receptor, you see a reduction in benefit. Perhaps the compounds are getting into an area of the brain with fenestrated capillaries like the arcuate nucleus.

Q: Could these compounds really be competitive antagonists that are decreasing the activity of native agonists?

A: We discussed this possibility early on. We’re certain now that it’s glucagon receptor agonism based on a number of studies. It’s really agonism, not relative antagonism.

Symposium: Technical Innovations in Islet Transplantation—Novel Approaches

Engineering Novel Encapsulation Platforms for Islets

Cherie Stabler, PhD (University of Florida, Gainesville, FL)

Dr. Cherie Stabler highlighted several novel beta cell encapsulation approaches that she views as particularly promising, including microencapsulation, nanoscale coatings, and new coatings created by covalent layer-by-layer encapsulation. She emphasized how these efforts can address several key considerations in the effort to fabricate nano-scale barriers to encapsulate pancreatic islets, such as ensuring a controllable thickness (through nanoscale control of capsule) and long-term mechanical stability (through covalently linking layers). According to Dr. Stabler, a “home run”  in encapsulation would involve resolving the immunological problem, the cell source problem, and the transplant problem. Islet encapsulation must solve issues of permeability, biocompatibility, and stability as well. The material must be permeable enough to allow nutrients such as glucose and oxygen to come into the islet and for insulin to leave the islet, while also being non-permeable to antibodies. Many materials degrade when put into the body, so the material must be stable enough to survive. In conventional microencapsulation, islets suffer from poor delivery of oxygen and nutrients, sluggish glucose response and insulin secretion, exacerbated by transplant site. ViaCyte has experienced some of these challenges firsthand in its phase 1/2 trial of PEC-Encap – due to the challenges with fibrosis and variable patient responses, the company has de-prioritized this effort to some extent and is instead focused on PEC-Direct, a direct vascularization product that does not protect ViaCyte’s stem cell-derived islet progenitor cells from the immune system (requiring patients to take immunosuppressants. We’re so very glad that very smart people like Dr. Stabler are hard at work at creating next-generation encapsulation devices that can hopefully avoid some of the pitfalls of the first-generation efforts.

Special Lectures and Addresses: National Scientific & Health Care Achievement Awards Presentation and Outstanding Scientific Achievement Award Lecture

Outstanding Scientific Achievement Award Lecture—Energy Sensing and Metabolism—Implications for Treating Diabetes

Gregory Steinberg, PhD (McMaster University, Hamilton, Ontario, Canada)

In a fascinating summary of his award-winning basic science research, Dr. Gregory Steinberg shared how his work on energy sensing and metabolic regulation could create exciting, novel therapies for diabetes treatment. Steinberg centered his talk around AMPK, a ubiquitous protein that is activated by metformin and exercise, and explained that this protein kinase is like a fuel gauge that tells the cell when to fill up with energy. He continued by explaining that increased AMPK levels may increase insulin sensitivity and glucose tolerance and reduce liver lipids. Simultaneously metformin also increases levels of GDF15, a protein that suppresses appetite.’ Steinberg explained that his most recent work has been in finding pharmacological agents that could activate these fuel gauges. He further suggested that AMPK is required for norepinephrine induced transformation of white adipose tissue into brown adipose tissue (BAT), based on evidence in mice lacking AMPK demonstrating that they are not able to regulate their own body temperature and develop insulin resistance despite eating the same diet as wild type mice. While there is no established method for restoring BAT activity in obesity and diabetes, Steinberg explained that that peripheral serotonin becomes elevated with high fat western diets and acts as brake to inhibit norepinephrine-induced activation of BAT. He noted that reduction of peripheral serotonin increases BAT activity and protects against obesity and insulin resistance in mice. Dr. Steinberg concluded his talk by circling back to his research’s relevancy to patients with type 2 diabetes, arguing that further examination of how to manipulate these cellular fuel gauges could lead to important, groundbreaking therapies in the treatment of type 2 diabetes.

Type 1 Diabetes Cures, Adjunct Therapies, and Pathophysiology

Symposium: Type 1 Diabetes Immune Intervention Trials

Type 1 Diabetes TrialNet Oral Insulin Trial – Introduction and Background

Jay Skyler, MD (University of Miami, FL)

Miami’s Dr. Jay Skyler explained how the TrialNet study came out of the DPT-1 oral insulin trial, which began in 1994. In DPT-1, oral insulin didn’t delay the development of type 1 diabetes. However, in this study, the inclusion criteria was initially confined to autoantibodies five standard deviations above the mean, but due to lagging enrollment, the team reduced the criteria to three standard deviations above the mean. In a post-hoc sub-analysis of only the patients who started with autoantibody concentration of at least five standard deviations above the mean, an extrapolation suggests that oral insulin delayed development by ~five years! Since this finding was purely hypothesis-generating, the TrialNet developed the current oral insulin study.

Type 1 Diabetes TrialNet Oral Insulin Trial – Results and Conclusions

Desmond Schatz, MD (University of Florida, Gainesville, FL)

Dr. Desmond Schatz presented mixed results from the TrialNet Oral Insulin study investigating the efficacy of oral insulin in delaying or preventing the onset of diabetes in relatives (mean age 8.6 years old) at risk for type 1 diabetes: The primary outcome, time from intervention to diagnosis in the primary stratum (participants with mIAA and ICA antibodies or both GAD65 and ICA512 antibodies and first phase insulin response [FPIR] above threshold), was negative – patients who received 7.5 mg oral insulin daily (n=198) progressed to diabetes at the same rate as those in the placebo group (n=184). The survival curves (below) are almost identical (HR=0.87, 95% CI: O.61-1.24, p=0.42), and on an annualized basis, rate of diabetes was 8.8% in the oral insulin group (58 individuals over six years) and 10.2% in the placebo group (62 individuals). However, it wasn’t all bad news for the hopeful audience. The TrialNet team pre-specified three secondary strata in which to explore the preventive effects of oral insulin. Two of them– (i) participants with mIAA and either GAD65 or ICA512 antibodies, FPIR above threshold (n=114) and (ii) participants with mIAA and either GAD65 or ICA512 antibodies, FPIR below threshold (n=2) – exhibited no difference in time to progression, just as the primary stratum did. But researchers saw an interesting signal in one of the secondary strata, participants with mIAA and ICA or both GAD65 and ICA512 antibodies, FPIR below threshold (same as primary stratum apart from FPIR level): Time to type 1 diagnosis was delayed in the oral insulin group (n=27) by an average of 31 months (2.5 years!) vs. the placebo group (n=27). Annualized rate of diabetes, per the survival curve below, was nearly cut in half, from 34.1% (19 progressions to diabetes in six years) to 18.1% (13 progressions) by the treatment (HR=0.45, 95% CI: 022-0.91, p=0.01). All of the four stratum and outcomes are shown in an excellent summary figure made by Stanford’s Dr. David Maahs. When all of the strata are collapsed and analyzed together, there was no difference in progression (annualized rate of 8.7% in oral insulin group, 10.4% in placebo; p=0.08). From a safety perspective, the therapy was well-tolerated – in 560 patients, there were no severe adverse events, and zero participants had a grade five adverse event (there was one instance of a grade four). This was truly a mammoth study, and our hats go off to the remarkable clinicians and staff at 87 locations who screened nearly 140,000 relatives to enroll 560 participants and gave this trial their utmost attention for 10 years.

• Dr. Schatz concluded his presentation of the results with one emphatic, make-no-mistake-about-it slide that simply read: “Monotherapy unlikely to prevent or delay type 1 diabetes.” Indeed, it’s seeming more and more clear that a cocktail of medications will be necessary to address the multiple sources of immune attack, ER stress, and other pathologies that trigger the onset of type 1 diabetes. See our notes from Dr. Jay Skyler’s ENDO 2017 talk for a list of type 1 prevention and intervention trials, many of which are combinatory in nature. Our type 1 diabetes cure and prevention competitive landscape also contains an overview of several ongoing efforts.
• We were hoping to hear a mechanistic speculation on what might be the driving the heterogeneity of results among patients with the same antibody background and differing only in FPIR, but it sounds like there is a lot to parse out – TrialNet PI Dr. Carla Greenbaum said in a press conference the day prior that she and her team were “flabbergasted” upon seeing an effect in the one secondary stratum. There was a working group meeting this morning to analyze future options. Dr. Greenbaum called attention to the fact that the participants in the second stratum who do progress to diabetes do so much faster, regardless of treatment group, than those in the other three groups. She suggested that there may be a “flare up” of the disease, as seen in MS and Crohn’s, during which immune intervention can prove beneficial. There’s obviously a lot of work to be done, but we’re definitely intrigued by this specific cohort.

Type 1 Diabetes TrialNet Oral Insulin Trial – An Oral Insulin Mechanistic Study

Peter Gottlieb, MD (University of Colorado, Aurora, CO)

In addition to the TrialNet study, Dr. Peter Gottlieb is conducting a trial with higher doses of oral insulin at the Barbara Davis Center. Participants are randomized to either 67.5 mg of oral insulin daily (n=45) or 500 mg bi-weekly (n=47) for six months, followed by six months of monitoring. The rationale is that the TrialNet study tested 7.5 mg (30/mg/m²), while the most effective dose in NOD mice was 300 mg/m². The Pre-POINT study suggested an immune signal at 67.5 mg daily (the human equivalent of the effective dose). The rationale for bi-weekly dosing was that the most effective regimen in mice was to give them the human equivalent of 600 mg/m² twice a week, not daily. Dr. Gottlieb speculates that activation of Treg cells may be more likely occur with intermittent dosing. Thus far, preliminary analyses on the first subjects in the trial suggest an increase in mIAA and reduction in GAA in those in the 67.5 mg/day group. Further analyses are underway. Dosing is one of the many banes of trials, especially in prevention – how is one to know how much and when to give an agent that could have a very small therapeutic efficacy window?

Type 1 Diabetes TrialNet Oral Insulin Trial – Independent Commentary

David Maahs, MD (Stanford University, Palo Alto, CA)

Dr. David Maahs’ independent commentary was largely positive – he pointed out that while the study was not the homerun that we had all hoped for, a pre-specified secondary hypothesis was met, and a 31-month delay to diagnosis could be viewed as a victory. He urged the audience to re-educate ourselves to accept incremental advances and to consider the perspectives of people living with diabetes – 31 months is two-and-a-half years without the burden of living with diabetes. For a young child, that could mean over 6,000 fingersticks not performed, and 930 nights during which a parent can sleep through the night without having severe hypoglycemia on the mind. Given that there was an observable effect in a portion of the participants, Dr. Maahs wondered if the cost of oral insulin is low enough to warrant further studies – the results demonstrate a step in the right direction, but is result significant enough to pour many more millions of dollars into the question? If yes, there is clearly a need for further hypothesis-driven mechanistic studies enriched for the responder stratum to better understand the pathophysiology. Another expensive, but we would argue worthwhile, effort would be to follow the participants who didn’t develop type 1 diabetes during the trial – how long does the protective effect last? And for those in the oral insulin group who did develop type 1 diabetes – will they have better outcomes vs. those in the placebo group? Dr. Maahs also explicated the need for better and cheaper assay techniques to make it more feasible to screen for antibodies and risk on a population-level, and also to lower the barriers of time and cost for these long-term prevention trials.

Questions and Answers

Q: I wonder if the delay observed in the stratum may have to do with timing – once you’re actually damaging the beta cells, you may be able to activate the immune system more?

Dr. Schatz: This gives us an opportunity to really study the mechanism. We’ve lumped all stages of type 1 diabetes together in the past – it was surprising to see the effect in the secondary stratum. They already lost FPIR. Is the immune response different at different stages of the disease? I think there’s evidence for that, but we have not conclusively shown there’s a difference. The hypothesis is you need some beta cell destruction, enhanced immune response, and you get a slight delay.

Dr. Yogish Kudva (Mayo Clinic, Rochester, MN): The SS1 cohort in the intervention group seems to be conflatable to clinical practice – what are the barriers? In an a priori designed study, this looks like a good effect?

Dr. Schatz: The primary stratum showed no effect in the population as a whole…Dr. Maahs talks about screening, and should oral insulin be used in a certain population. I think, if it’s safe and cheap and does no harm, there will be some people, who we need to figure out their responses. I personally think if it’s safe, we’ll use combo therapy in the future, but this study showed it couldn’t be used in primary stratum. That study was negative. We need to understand more about the secondary stratum. And those in the primary stratum who had no benefit, who are now in the secondary stratum – would they benefit?

Q: Have to come back and say, is this question of heterogeneity? How are those patients in the second stratum different? It might be something other than timing, and we don’t want to miss that.

Dr. Schatz: These are obviously post-hoc analyses. What we got to do as a group is to define responders and do personalized medicine in the future, but these are hypothesis-generating. We need to take a look at how we do studies.

Imatinib (Gleevec) in New-Onset Type 1 Diabetes—Background and Results

Stephen Gitelman, MD (UCSF, San Francisco, CA)

Opening with the question “What can we do to make beta cells great again?” UCSF’s Dr. Stephen Gitelman presented results from a JDRF-backed phase 2 study of Gleevec (Imatinib) in adults recently diagnosed with type 1 diabetes (n=67). Gleevec is a tyrosine kinase inhibitor commonly used to treat leukemia and other cancers – several case reports and other studies have suggested a possible type 1 diabetes benefit in patients being treated for cancer, which has been substantiated in NOD mouse models. Participants received either 400 mg of Gleevec (n=45) or placebo (n=21) for six months, followed by six months of follow-up – over the year, the primary outcome, C-peptide AUC during a mixed meal tolerance test, declined steadily in the placebo group, while the group that received Gleevec followed the same trajectory for the first few months, before diverging and ending up with a statistically significant increase by month 12 (~0.6 nmol/l vs. ~0.5 nmol/l; p=0.05). Insulin use increased steadily over time in both groups, but to a greater degree in the placebo group (+~0.15 units/kg/day vs. +~0.02 units/kg/day; p=0.049). Interestingly, dose initially dipped in the treatment group, but then climbed more or less in parallel with the placebo group, indicating there might be a short window where Gleevec turns the clock back on insulin dependence. There was no difference in A1c over the course of the trial (everyone was treated to a target of <7%), and likewise no difference in the distribution of adverse events between Gleevec and placebo (though Gleevec did contribute to a marked increase in GI symptoms). In Q&A, Dr. Hans de Vries questioned why the statistical testing was all one-tailed, rather than two-tailed, as is commonly seen in a placebo-controlled study. Dr. Gitelman responded that his team wanted to get a sense of whether Gleevec would be beneficial in adults, before moving to kids (the ideal target, but FDA required evidence of prospective benefit in adults first), and had a limited budget. Significance is lost if the test is two-tailed, but we believe there is still enough of a signal here to warrant future research in pediatrics: The drug is relatively safe, and children would likely have a greater mass of beta cells that can be salvaged. Next up, Dr. Gitelman hopes to complete a per- protocol analysis, identify responders, and partition the effects of age in the 18-45 year-old study population (a greater effect in younger patients would suggest that Gleevec would be even more beneficial in children). He also wishes to conduct mechanistic studies and follow the subjects out to 24 months.  

• We are highly intrigued by the fact that the beneficial effects of Gleevec appear to maintain, even augment, over the six months following the cessation of treatment. While we, nor Dr. Gitelman, don’t really know what is going on here, the lasting effect is certainly a clue as to how Gleevec is exerting its effect – epigenetic mechanisms? Immune re-training? Future mechanistic studies will be interesting to follow. Based on previous literature, we know that Gleevec could be working through mechanisms involving anti-inflammation, ER stress, and insulin sensitivity. In a brief interview, Dr. Gitelman proposed that it may have to do with dampening the unfolded protein response, which results in beta cell apoptosis. If this is the case, the way it translates to long-term protection (after dosing has stopped) is still a mystery, and we wonder about potential off-target effects.

DIAPREV-IT Trial with GAD-Vaccine—Results and Conclusions

Helena Larsson, MD, PhD (Lund University, Sweden)

Lund University’s Dr. Helena Elding Larsson shared the disappointing results of the DiAPREV-IT trial of Alum-GAD in children ages 4-18 with multiple IAAs but no diabetes (n=50): While the primary objective of safety was met, there was no significant effect on progression to diabetes in any of the groups included in the study. Children were randomized to receive two 20 ug doses of subcutaneous Alum-GAD (n=25) or placebo (n=25) 30 days apart. The survival curve shows that the intervention had no tangible impact on progression (HR=0.77; p=0.574). Overall, at inclusion, 26/50 had impaired glucose tolerance, and in the follow-up, 36% had been diagnosed with type 1 diabetes – fewer than expected. Further analyses showed that, regardless of stratum (two antibodies, three to six antibodies) or baseline glucose tolerance, the absence of delayed progression held. These are disappointing findings, but Dr. Larsson pointed out that the study was small and therefore not powered for subgroup analyses – future mechanistic studies will examine pathologic effects in cellular and humoral samples. On safety, there were no study related adverse events, increased risk of celiac or thyroid autoimmunity, signs of accelerated progression to type 1 diabetes, and while GADA titres increased in children treated with Alum-GAD, there was no effect on other IAAs. Despite a negative result, the successful safety outcomes shown here could prove useful in future studies investigating alternative dosages or combinational approaches.

• Despite its storied and promising history, GAD-induced immune tolerance has not delivered at this point. Boston Children’s Hospital’s Dr. Joseph Wolfsdorf asked whether we should continue to investigate it as a therapeutic option. While he doesn’t know the answer, it clearly keeps him up at night. “Imagine in the 1930s,” he began, “when penicillin was discovered. It kills bacteria in a petri dish, so they started a trial with penicillin to kill streptococcal pharyngitis in the throat, 5 mg/day. What if the dose had been in the completely wrong universe? Are we struggling to make headway here because we don’t know how to dose the therapy?” It’s anyone’s guess at this point…

Symposium: Results of the JDRF Reducing with Metformin Vascular Adverse Lesions in Type 1 Diabetes (REMOVAL) International Multicenter Trial

Introduction, Study Rationale, and Design

Helen Colhoun, MD (University of Edinburg, UK)

The REMOVAL trial was published online in Lancet Diabetes & Endocrinology just as this symposium began, and Dr. Helen Colhoun opened by outlining motivations for the trial and reviewing study design. She highlighted a lingering and concerning problem in type 1 diabetes care – patients face a 2.5-4x risk for CV disease compared to a background population, without adequate adjunct therapies to address it. Metformin is prescribed for some type 1 patients and is recommended in ADA and other treatment guidelines. However there have only ever been nine small studies, the largest of which studied was in 100 participants followed for one year (a total randomized follow-up in all studies of 192.8 patient years).  The evidence summarized in a meta-analysis published in 201o by Dr Colhoun and Dr Petrie demonstrated insulin-sparing effects, weight loss benefits, and possible A1c-lowering efficacy. There was a slight impact on LDL in one previous study in which few patients were treated with statins.  DCCT/EDIC, is the only study that has showed a long-term benefit on macrovascular complications in type 1, stemming from intensive glucose-lowering, but risk factors other than glycemia are correlated with CV outcomes, so metformin might lower frequency of CV events by impacting other risk factors or by other pleiotropic effects as in type 2 diabetes.  Ambiguity surrounding metformin’s mechanism of action means that much remains unknown about the molecule’s specific effects on different physiological systems. All of this possibility led the REMOVAL research team to select this well-known generic drug for a CV study. The group decided to look at an intermediate marker of CV risk, carotid intima media thickness (cIMT), as a proxy for potential long-term cardioprotection. Adults ≥40 years-old with type 1 diabetes (n=428) were randomized to twice-daily metformin at a 1,000 mg dose (n=219) or to placebo (n=209), both on top of standard of care (which included insulin titration/adjustments). Treatment and data collection continued for three years, following an initial three-month run-in period of insulin optimization. The primary outcome was rate of progression of mean far wall cIMT at baseline, 12 months, 24 months, and 36 months. Secondary outcomes included A1c, LDL cholesterol, albuminuria, weight loss, insulin dose, and endothelial function. Rate of progression to maximal cIMT was a pre-specified tertiary endpoint.

Study Population

Alicia Jenkins, MD (University of Sydney, Australia)

REMOVAL studied 428 middle-aged adults with long-standing type 1 diabetes at high risk of cardiovascular disease, as defined by three or more risk factors (including BMI >27 kg/m3, A1c >8%, known cardiovascular or peripheral vascular disease, current smoker, high blood pressure, high cholesterol or triglycerides, strong family history of cardiovascular disease, or diabetes duration >20 years). Baseline characteristics were well-balanced between the metformin and placebo-treated arms in terms of age (55 and 56 years), diabetes duration (33 and 34 years), BMI (28 kg/m3), A1c (8.1% and 8.0%), total daily insulin dose (0.63 and 0.68 units/day), frequency of prior cardiovascular disease (14% and 11%), blood pressure (systolic: 130 and 129 mmHg; diastolic: 73 and 72 mmHg), and cholesterol (LDL=85 mg/dl and HDL=62 mg/dl for both groups). Notably the study population had high rates of retinopathy: only 12% of participants in the metformin arm and 8% of participants in the placebo arm had no form baseline retinopathy, with the rest of the population showing high incidence of non-proliferative diabetic retinopathy (64% and 63%), inactive proliferative diabetic retinopathy (16% and 19%), and proliferative diabetic retinopathy (7% and 9%). On the renal front, the majority of participants in the metformin and placebo arms alike had normal eGFR (58% and 62%), though there was some incidence of stage 1 CKD (11% in both groups), stage 2 CKD (27% vs. 23%), and stage 3a CKD (3% and 4%). Furthermore, the study population had high usage of statins (82%), antihypertensives (73%), and anti-platelet drugs (39%).

Glycemia

Irene Hramiak, MD (St. Joseph’s Healthcare, Ontario, Canada)

Dr. Irene Hramiak took the stage to discuss the impact of metformin on A1c and insulin dose in the three-year REMOVAL trial. From a baseline of 8%, patients on metformin experienced a mean A1c decline 0.24% greater than patients on placebo after three months (p<0.0001). After 36 months, this treatment difference was 0.13% in favor of metformin (p=0.006), though A1c had risen above baseline for both groups. Dr. Hramiak characterized this effect as “small, but highly statistically significant,” calling attention to the steep slope of glucose-lowering in the first three months, even though the benefit appeared to dissipate with follow-up.

• Average daily insulin dose grew for participants in the placebo arm but decreased for participants in the metformin arm over three years, culminating in a “modest” treatment difference of 1.9 units/day (p=0.0018). Of note, a majority of patients enrolled in REMOVAL (58%) were on a background of basal bolus therapy, while 33% were on an insulin pump, 3% were on twice-daily basal insulin, and 5% were on some other insulin regimen.
• The hazard ratios for minor and severe hypoglycemia were 1.12 and 1.23 in favor of placebo at the 36-month mark, but neither of these reached statistical significance (p=0.259 and 0.442, respectively), leading Dr. Hramiak to conclude that metformin did not increase risk for hypoglycemia. While this is important data to report from a safety perspective, one of the reasons we’re pushing for better adjunct therapies in type 1 diabetes is that we want to lower a patient’s insulin dose and thereby reduce hypoglycemia – a point estimate in the “wrong direction” is somewhat disappointing in this context. We might’ve hoped for a significant hypoglycemia benefit in REMOVAL, but we recognize that insulin dose wasn’t drastically decreased with the addition of metformin by any means (Dr. Julio Rosenstock argued during Q&A, a change of ~two units per day is “absolutely nothing”). All in all, these glycemia results were disappointingly neutral. We’re hesitant to give up on metformin’s role in type 1 diabetes care and treatment algorithms (see the Q&A section below for a deeper dive on this topic), but as acknowledged by the REMOVAL investigators, and contrary to current guidelines, metformin did not offer a clinically-meaningful benefit to A1c on top of insulin therapy.

Primary Endpoint

Nishi Chaturvedi, MD (University College London, UK)

REMOVAL’s primary endpoint was mean carotid intima media thickness (cIMT), a commonly-used surrogate marker for cardiovascular risk. cIMT essentially reflects the thickness of the inner two layers of the carotid arteries (atherosclerosis) and can be measured by careful and quality assured noninvasive ultrasound techniques. Over the course of the three-year study, mean cIMT increased at a rate of 0.006 mm/year in the metformin-treated group vs. a faster 0.010 mm/year rate of increase in the placebo group, though this trend did not reach statistical significance (p=0.1664). However, the related tertiary outcome of maximal cIMT increased at a significantly slower pace in the metformin-treated group (0.012 mm/year) than the placebo group (0.25 mm/year; p=0.0093).  In biological terms, mean cIMT reflects overall thickening of the wall of the artery, while maximal cIMT, favored by the DCCT-EDIC investigators, includes areas of plaque and focal thickening.

Clinical and Metabolic Outcomes

John Petrie, MD (University of Glasgow, Scotland)

Dr. John Petrie, primary author of the study, presented secondary endpoint data. From a baseline 84 kg (185 lbs), body weight decreased for patients on metformin and increased for patients on placebo, leading to a treatment difference of 1.2 kg (2.6 lbs) sustained over three years (p<0.0001). Metformin also demonstrated positive effects on LDL, which fell 5 mg/dl in the treatment group but remained flat in the placebo group at year three (p=0.0117) and on eGFR – this measure of renal function rose sharply for people on metformin in the first three months, and after 36 months showed a treatment difference of 4 ml/min/1.73m² in favor of metformin (p<0.0001). In less positive news, metformin was not associated with a statistically significant benefit to retinopathy or to endothelial function.

• The signals for weight loss and lipid-lowering efficacy support metformin’s current niche in type 1 diabetes care, in that many HCPs prescribe the generic drug to their type 1 patients to mitigate insulin-induced weight gain in those with overweight or obesity. During Q&A, Dr. Partha Karr shared that these findings provide some reassurance on how he runs his practice and when he turns to metformin for type 1, which is most often for a patient who also wants to lose weight or improve cholesterol. Looking at REMOVAL through this lens, the results still spotlight metformin’s value and utility in type 1 diabetes management, although they don’t bring to light any new benefits to CV biomarkers or glycemia.

Safety

Martijn Brouwers, MD (Maastricht University Medical Center, Maastricht, Netherlands)

Dr. Martijn Brouwers stepped up next to discuss additional safety outcomes of interest. Treatment discontinuation was significantly higher among participants treated with metformin (41 cases, amounting to 27%) than placebo (19 cases, amounting to 12%; p=0.0002), and accordingly total adverse events occurred significantly more frequently in the metformin-treated group (27% vs. 12%; p<0.001). As expected with metformin, gastrointestinal issues were the most commonly reported adverse events, occurring in 16% of metformin-treated patients versus 3% of those in the placebo group (p<0.001). Additionally, vitamin B12 deficiency occurred significantly more frequently in the metformin-treated group (12%) than the placebo group (5%), translating to a significant elevation in vitamin B12 deficiency risk (HR=2.76; p=0.0094). Dr. Brouwers noted that vitamin B12 deficiency is a known side effect of metformin; the long-term effects of this kind of vitamin B12 deficiency are unclear but if undetected may include aggravation of sensory neuropathy. The REMOVAL data add to a body of evidence that Vitamin B12 should be monitored  during long term metformin therapy: this is rarely done in routine clinical practice.  Finally, there was no increase in hypoglycemia between either treatment arm, and serious adverse events were equivalent between the metformin group (16%) and placebo group (15%).

Conclusions

Peter Rossing, MD (Steno Diabetes Center, Copenhagen, Denmark)

Dr. Peter Rossing provided a helpful summary of the conclusions from each presentation that came before his. He emphasized that REMOVAL is the largest and longest trial of metformin in type 1 diabetes, and that it’s the first RCT to look at an intermediate variable for CV outcomes (this has to do with feasibility, since a traditional CVOT for metformin in type 1 is currently considered too large an investment for diabetes funding agencies). Despite an underwhelming result on the primary endpoint, Dr. Rossing positioned the statistically significant benefit to tertiary endpoint (maximal cIMT) as an exciting piece of data, perhaps one to explore further. He reiterated the significant benefits to metformin in terms of weight loss and (modestly) reduced insulin dose. REMOVAL results do not support the assertion in current treatment guidelines that metformin causes a clinically-meaningful improvement in glycemic control, Dr. Rossing explained, but they do suggest that metformin could have a broader role in CV risk management due to the weight loss, LDL-lowering, and slower progression to maximal cIMT. This latter point is a bold claim for clinical trial purists, since metformin did not show statistical significance on the primary endpoint of rate of progression to mean cIMT. That said, there have been no cardiovascular outcome trials to date in type 1 diabetes, so we agree with the Commentary in the Lancet Diabetes and Endocrinology that hope is still alive for metformin in better management of type 1 diabetes/CV complications.  For one, the generic drug is not going anywhere anytime soon, and it’s a widely-accessible therapy known to be effective in type 2 diabetes. In addition, we’d love to learn more about how elements of trial design could have skewed or muted efficacy findings. For example, a majority of participants were already well-treated with statins and blood pressure-lowering medications at baseline (which will be hard to avoid in selecting a real-world patient population), and this may have made it more difficult to demonstrate statistically significant benefit on a CV biomarker. Dr. Bill Tamborlane, who chaired the symposium, hinted during Q&A that cIMT may not be the ideal surrogate for CV outcomes, since it didn’t appear after six years of DCCT follow-up and thus may not be sufficiently “timely.” Another point raised during Q&A was that cIMT was already quite “favorable” at baseline, which may have made it more challenging to show an simprovement. These ideas are purely speculative right now, and we’ll leave it to the statisticians and other thought leaders to weigh in on REMOVAL at future meetings. Dr. Petrie announced that there will definitely be another symposium dedicated to this type 1 trial at EASD 2017 in Lisbon, Portugal.

Perspective

Naveed Sattar, MD (University of Glasgow, Scotland, UK)

As commentator, Dr. Naveed Sattar set out to contextualize the REMOVAL results. He set the stage with a discussion of cardiovascular disease in type 1 diabetes. Recent data from a Swedish registry study demonstrates that individuals with type 1 diabetes and no CV risk factors have an 82% greater risk of a CV event than their counterparts in the general population – and yet there are no CV disease primary outcome studies in type 1 diabetes. Against the backdrop of this severe unmet need, the implications of the REMOVAL trial are frustratingly unclear. In Dr. Sattar’s view, a CV benefit is “suggestive but not conclusive” in REMOVAL, making it very unclear whether metformin should be recommended to people with type 1 diabetes to slow the progression of CV disease. On whether further trials are warranted to assess metformin for CV disease in type 1 diabetes, Dr. Sattar was torn. Though metformin is inexpensive and generally safe, making for relatively easy logistics, it seems as though other adjunct therapies (such as SGLT-2 inhibitors and GLP-1 agonists, which have demonstrated cardioprotective effects in type 2 diabetes) are better positioned for this large-scale investment of time and resources (though we’re less optimistic about the future of GLP-1 agonists in type 1 diabetes, given the safety signals in the ADJUNCT trials for liraglutide – though we believe some of this may have been due to trial design and dosing decisions). During Q&A, SGLT-2 inhibitors in particular were highlighted for their potential in type 1 diabetes and the chance that they may confer superior glycemic and CV benefits over metformin. We’re intrigued by this possibility, and we’re closely following Lilly/BI’s and AZ’s and Lexicon’s phase 3 programs for an SGLT-2 in type 1 and/or an SGLT-1/2. Despite REMOVAL’s somewhat underwhelming results, Dr. Sattar closed by reminding the audience of the significance of this undertaking as the single largest and longest randomized trial ever to examine a CV parameter of any sort in type 1 diabetes. We certainly hope it isn’t the last and to the point raised in Q&A, big funds are needed to invest in this (but that are a pittance compared to funds spent each year on avoidable complications).

Panel Discussion

Dr. Bill Tamborlane (Yale University, New Haven, CT): You talked a lot about LDL changing. I’d like to think about what wasn’t said. What happened to HDL?

Dr. Petrie: We saw very similar changes.

Q: One of the things that determines ability to see changes in cIMT is baseline cIMT. Your patients, I have to say, were extremely well-treated at baseline. To what extent do you think that messed up your power calculation? It’s hard to show improvement in endothelial function, as well, if at baseline you already have good endothelial function.

Dr. Hramiak: That’s a good point, that baseline cIMT was favorable. These patients were actually surprisingly well-treated on statins and blood pressure-lowering medications. Certainly, baseline values were lower than expected, and then rate of progression for mean cIMT was lower than anticipated from data from younger DCCT-EDIC patients and from other conditions.

Comment: Of course, because that’s where the lesion is. I recall another study that had low cIMT at baseline and the group made an incorrect negative conclusion about ezetimibe. You’re hurt by this in REMOVAL, I think.

Q: Are these participants a selected group of survivors? They have 32-33 years of T1D…what fraction of people would have already died of CVD before this time point?

Dr. Colhoun: By definition all cohorts are survivor cohorts, unless you begin the study from birth. If you’re asking if this was a population that was depleted of events – I don’t think so. A more interesting question is why in a population where event rates are fairly substantial do we not see substantially abnormal cIMT.

Q: cIMT is like tree rings, so the effect should persist. Will there be a data registry for these participants to see if the changes in cIMT we see at three years will become meaningful later?

Dr. Petrie: We have approval to follow these patients up in longer term. It will take a long time, but we certainly got that approval. As you say, they’re no longer on randomized treatment so we would be looking for a “metabolic memory” effect.

Dr. Julio Rosenstock (UT Southwest, Dallas, TX): I want to commend all the investigators. It takes a lot of work to do these kinds of studies, especially with a retinopathy component. There’s a real need for adjunct therapy in type 1 diabetes. But looking at the results of this trial, I basically see a negative study from all perspectives, not just the primary endpoint. You’re being generous on a potential reduction in CV events based entirely on a tertiary outcome. You’re using the word “modest” too much – two units is absolutely nothing in terms of reduced insulin dose. Yes, metformin is out there and it costs $2 at Walmart. But we need to raise the bar. This study would have been promising 10 years ago, when we didn’t have any other options, but now the SGLT-2 class has potential in type 1 diabetes. I take your word that a CVOT will one day be necessary for type 1. I hope this stimulates potential for a large outcomes trial of SGLT-2 inhibitors in type 1 diabetes, but metformin was totally negative in this trial.

Dr. Colhoun: Raise the bar? What we actually need to do is raise the money. There has never been a CVD outcomes study in the type 1 diabetes population for this reason.

Dr. Rosenstock: I agree with that, but metformin is not the drug. An SGLT-2 inhibitor or GLP-1 agonist would be the drug – certainly not metformin.

Dr. Colhoun: In our paper in Lancet we are certainly not claiming that this is a positive trial. We need a sustained and substantial effort to really drive forward a much higher standard and larger trials with CVD endpoints in type 1 diabetes. We spent a lot of time trying to raise the money to do a CVD outcomes trial with metformin, and it was extremely challenging. Let’s hope it happens someday. What we have done in this trial is create a very good network to show that trials  with a cardiovascular focus can be done in T1D, which is something people have been skeptical of.

Dr. Tamborlane: In the DCCT after six years of follow-up, cIMT differences were basically zero. This speaks to an issue about choice of surrogate outcome. Carotid thickening may not be timely enough to be able to show an effect.

Dr. Petrie: Ultimately, this is the study we designed after a lot of workshop with JDRF, and this is the outcome we chose. Treatment guidelines in the US and UK say you should use metformin for people who have type 1 diabetes and obesity to try and improve their glycemic control. One message from REMOVAL is that you should not – there’s not much of an effect on glucose control. It’s transient, though it’s statistically significant. So, REMOVAL changes our perspective on metformin for type 1 diabetes, pointing us to maybe investigate more cardiovascular effects.

Q: Did you look at sex differences within the groups? I ask because in the T1D Exchange study, the boys had an improvement but the girls did not (and the boys were more abnormal at baseline so maybe had more room to change).

Dr. Petrie: We haven’t looked into that, but we could do it easily.  We need to prioritize a few key post hoc questions so as not to over-interpret the subgroups -  this could be a good one.

Q: From a clinician’s perspective, why was metformin chosen and not an alpha-glucosidase inhibitor?

Dr. Petrie: As you know there is a large CVOT involving alpha-glucosidase inhibitors going on in China right now led by the Oxford group, with results expected reasonably soon. The study includes people with prediabetes.  In my view, there’s not enough data on alpha-glucosidase inhibitors in type 1 diabetes to justify this kind of trial. All these hypotheses are interesting and we’d love to see many trials for cardiovascular outcomes associated with different agents in type 1 diabetes – in fact we’d like to see any trial assessing this in type 1 diabetes – but if one trial is to be done it will likely be with an SGLT-2 inhibitor, if phase 3 data in type 1 diabetes is promising and shows adequate safety.  (Editor’s note – we’d love to see a CVOT with multiple therapies.)

Dr. Partha Kar (Portsmouth Hospitals, UK): Based on these results, as clinicians, would you prescribe metformin to your patients with type 1 diabetes at high CV risk?

Dr. Hramiak: Probably not. I’m more convinced that in adolescents who are more insulin-resistant and who have weight issues, we should prescribe metformin because they’ll see more benefit in terms of minimizing insulin dose. Hypoglycemia is a huge limiting factor of insulin, which is why we’re looking for adjunct therapies in the first place. Weight loss is also ideal. But to Dr. Rosenstock’s point: adjunct therapies in type 1 to-date have had trouble proving glycemic benefits beyond 0.2-0.3% A1c reductions, so we’re looking for something other than glycemic benefits. We have to combine outcomes as we did in this trial – it’s not just about glycemia, and it’s not just about CV disease.

Dr. Sattar: What would you do?

Dr. Kar: I already use metformin in the way you describe, so I don’t think REMOVAL will change my practice. Right now, I use metformin in type 1 patients who are overweight, so this just gives me more reassurance. I wasn’t expecting a huge CV benefit per se, and I think cIMT is an ambitious endpoint for a three-year study. But I won’t say this is a completely negative trial, because it confirms my use of metformin in the patients I’ve got.

Dr. Tamborlane: Metformin seems to have some effect, but its borderline. GLP-1 agonists are also being studied in type 1 diabetes. You really get substantial weight loss with these agents which may have an advantage that goes beyond just glycemic control. Another great hope is SGLT-2 inhibitors. It’s been a challenge to find drugs with cardioprotective effects for people with type 1 diabetes, but we’re still hoping that the holy grail is out there somewhere.

Dr. Chaturvedi: Is cIMT a poor outcome since it’s a surrogate? At the moment it is one of the best surrogates we have for cardiovascular endpoints that both predicts endpoints and can be employed easily in large clinical settings. We were not expecting an effect on cardiovascular risk through glycemia lowering alone, we were anticipating pleiotropic effects. Lastly, the effects we saw in the cIMT measures in this trial were actually greater than those shown in the DCCT trial. The DCCT trial saw modest effects on cIMT but quite striking reductions in cardiovascular outcomes ultimately. This is to say that it’s a bit unfair to criticize the endpoint we used. The effects on cIMT we saw here aren’t completely negligible.

Dr. Tamborlane: A lot of these patients were on statins, and a lot were on anti-hypertensive medications. We saw very little use of these agents in the DCCT. It’s hard to parse what the confounding effects of these other drugs may be. I would also suggest that another mistake is calling this study “REMOVAL,” because you didn’t remove anything. Maybe you should have called it the SLOW IT DOWN study.

Q: Did you compare the results between people who were obese vs. non-obese at baseline?

Dr. Petrie: These data are quite fresh, so we haven’t looked into that yet. This could be one to prioritize for post hoc analysis – we will present theses at EASD.

Dr. Calhoun: I take your point that DCCT-EDICT trial did in the end teach us about cardiovascular endpoints, but we can’t realistically wait 30 years to see if diabetes drugs have an impact on cardiovascular disease. The take-home message is that we’re trying to cut short answers to these big questions by doing small studies in type 1 diabetes with surrogate outcomes like cIMT. This will probably not resolve our clinical equipoise sufficiently, but it does tell us something. Perhaps Dr. Rosenstock is actually going to raise the money to do a large CVOT.

Q: The 1,000 mg dose of metformin isn’t particularly big, and it’s a lot less than what was used in DCCT and UKPDS. Is there any plan to do a protocol analysis on dose?

Dr. Petrie: I think we can do an analysis like that. We have an estimate of the dose of metformin taken by each participant over their time in the study based on tablets distributed and  returned. An important clinical message: when you give people 2,000 mg of metformin, you’re actually giving them less, because some patients will experience gastrointestinal adverse effects. We could look at subgroups of patients who tolerate metformin better. If you’re not experiencing side-effects (especially GI), and metformin might improve your CV risk profile and it might control your weight, why not take it?

Dr. Tamborlane: This has been a great discussion with terrific questions – one of the more enjoyable sessions I’ve been at.

Oral Presentations: GLP-1s and SGLT2s—To Do or Not to Do in Type 1 Diabetes Mellitus?

Twenty-Four-Week Efficacy and Safety of Sotagliflozin, a Dual SGLT1 and SGLT2 Inhibitor, as Adjunct Therapy to Insulin in Type 1 Diabetes (inTandem1)

John Buse, MD (UNC, Chapel Hill, NC)

UNC’s Dr. John Buse presented full data from the phase 3 inTandem1 trial, elucidating the benefit-risk profile of SGLT-1/2 dual inhibitor sotagliflozin in type 1 diabetes. inTandem1 was a double-blinded trial that randomized 793 patients to either placebo, sotagliflozin 200 mg, or sotagliflozin 400 mg. The trial included a six-week insulin optimization period prior to randomization. As was reported in the topline results, even in the context of optimized insulin, the trial impressively met its primary endpoint by producing a mean placebo-adjusted A1c reduction of 0.35% in the 200 mg arm (baseline A1c post-optimization=7.6%; p<0.001) and 0.41% in the 400 mg arm (baseline A1c post-optimization=7.6%; p<0.001) at 24 weeks. inTandem1 employed a hierarchical statistical testing structure, in which secondary endpoints were assessed in the following order: (i) “net benefit” (defined as target A1c<7% with no severe hypoglycemia or DKA); (ii) weight; (iii) bolus insulin dose; (iv) fasting plasma glucose (FPG); and two measures of patient-reported outcomes – (v) the Diabetes Treatment Satisfaction Questionnaire status (DTSQ) score; and (vi) the two-item Diabetes Distress Screening Scale (DDS2) questionnaire score. We previously learned from a second release of topline data from inTandem1 that the 400 mg dose demonstrated superiority to placebo for all of these secondary endpoints, while the 200 mg dose only demonstrated superiority for A1c, net benefit, and weight. Dr. Buse very excitingly provided new detail on these secondary outcomes. More than twice as many patients achieved net benefit on sotagliflozin 400 mg compared to placebo: 44% of participants in the 400 mg arm achieved “net benefit” at week 24, compared to just 22% of those in the placebo arm (p<0.001). Those in the 200 mg arm also substantially more likely to achieve net benefit – 34% (p=0.002 vs. placebo). As was shared in the topline results, patients taking sotagliflozin experienced a 1.6 kg (3.5 lbs) and a 2.7 kg (6 lbs) weight reduction at 24 weeks with the 200 mg and 400 mg doses, respectively – this compares to a mean weight gain of 0.8 kg (1.8 lbs) in the placebo group (p<0.001). The results shared today revealed that the superiority of sotagliflozin 400 mg for the other secondary endpoints was similarly highly statistically significant (p<0.001). On the other hand, Dr. Buse noted that there was some heterogeneity between the impact of the two doses on bolus insulin dose – while sotagliflozin 400 mg was associated with a statistically significant decrease in bolus insulin (p<0.001; exact dosages not shared), there was no statistically significant difference in bolus insulin dose among those treated with sotagliflozin 200 mg and those in the placebo arm. On the other hand, the p-value for the difference between the 200 mg arm vs. placebo was below 0.05 for FPG (p=0.036), DTSQ score (p<0.001), and DDS2 score (p=0.002). That said, because of the hierarchical nature of the statistical testing, Dr. Buse emphasized that these findings may only be characterized as “descriptive” rather than significant. While some more conservative clinical trial purists may make a big deal about this, we’re very, very pleased to see consistency between the 400 mg and the 200 mg dose for these very critical endpoints. We’re especially excited about the quantification of the quality of life and patient satisfaction benefits of this drug – anecdotally, we’ve heard rave review from patients with type 1 diabetes taking selective SGLT-2 inhibitors and we’re glad to see this backed up with hard data. Safety data was as reported in the topline results, with fairly balanced adverse event rates across all three arms, somewhat higher rates of DKA with sotagliflozin, and somewhat lower rates of severe hypoglycemia. While there is some concern in some quarters about type 1 patients taking this class, we don’t think there is a way to stop it – it may be valuable to look at gaps in therapy for type 1s in order to better understand patients taking SGLT-2s off label. We applaud Lexicon for collecting so many outcomes and hope that these will be standardized soon. 

inTandem1 Primary and Secondary Efficacy Endpoint Results

Endpoints	Sotagliflozin 200 mg (p-value vs. placebo)	Sotagliflozin 400 mg (p-value vs. placebo)	Placebo
A1c	-0.43% (p<0.001)	-0.49% (p<0.001)	-0.08%
Net Benefit (proportion of patients with A1c<7% and no severe hypoglycemia or DKA)	34% (p=0.002)	44% (p<0.001)	22%
Weight	1.6 kg (3.5 lbs, p<0.001)	2.7 kg (6 lbs, p<0.001)	0.8 kg (1.8 lbs)
Bolus insulin	Undisclosed (p=0.10)	Undisclosed	Undisclosed
Fasting plasma glucose (FPG)	Undisclosed (p=0.036)	Undisclosed (p<0.001)	Undisclosed
Patient-reported Diabetes Treatment Satisfaction Questionnaire status (DTSQ) score	Undisclosed (p<0.001)	Undisclosed (p<0.001)	Undisclosed
Patient-reported Diabetes Distress Screening Scale (DDS2) score	Undisclosed (p=0.002)	Undisclosed (p<0.001)	Undisclosed

inTandem1 Safety Results

	Sotagliflozin 200 mg	Sotagliflozin 400 mg	Placebo
Proportion of patients with ≥1 treatment-emergent adverse events	67%	71%	68%
% patients with diarrhea	7%	10%	7%
% patients with genital mycotic infection	6%	10%	3%
Number of patients with DKA	3 (1.1%)	8 (3.1%)	0
Number with severe hypoglycemia	11 (4.2%)	12 (4.6%)	6.7%)

A 12-Week Dose-Ranging Study of Sotagliflozin, a Dual SGLT-1 and SGLT-2 Inhibitor, as Adjunct Therapy to Insulin in Type 1 Diabetes (inTandem4)

Paul Strumph, MD (Lexicon Pharmaceuticals, The Woodlands, TX)

Lexicon VP of Clinical Development Dr. Paul Strumph also took to the stage to discuss full results from the phase 2 dose-ranging inTandem4 study of sotagliflozin. The double-blinded, 12-week trial randomized 141 patients with type 1 diabetes to three doses of sotagliflozin (75 mg, 200 mg, or 400 mg), plus placebo. Unlike the phase 3 inTandem1 trial, inTandem4 only included a two-week placebo run-in period, rather than a six-week insulin optimization period.  The vast majority of the numeric data was already shared in the topline results, though Lexicon shared p-values for the first time, demonstrating that these results were highly statistically significant. The primary endpoint A1c results as well as the secondary urinary glucose excretion, postprandial glucose, body weight, fasting plasma glucose (non-inferior), and blood pressure results are summarized in the table below. Very notably, however, Lexicon shared data on beta-hydroxybutyrate (BHB) levels at baseline and at week 12 – as a measure of ketogenesis, BHB measurements are very helpful as we consider the potential DKA risk of sotagliflozin. Notably, the mean increase in blood BHB at week 12 was only 0.1 mmol/l, which is the lowest value detectable by a point of care BHB meter. Dr. Strumph also noted that this level of BHB increase is lower than what is typically seen with selective-SGLT-2 inhibitors. Overall incidence of DKA was very low this trial, with the only case of DKA in the entire trial occurred in the 400 mg arm – though, very notably, the patient who experienced DKA chose to continue the study after the event, demonstrating that the perceived benefits outweighed the DKA risk for this patient. Although just one case, this is unsurprising to us. The level of DKA observed in both inTandem4 and inTandem1 is somewhat lower in all arms than might be expected in a general type 1 diabetes population. Dr. Buse noted during Q&A following the inTandem1 presentation that all participants in the trial were very carefully and intensively educated on DKA risk management. Our sense is that this level of intensive education rarely happens in the “real-world,” and we hope that Lexicon will continue its leadership in pairing sotagliflozin with appropriate educational efforts when the product launches. Write Richard Wood of dQ&A for more on overall level of understanding by patients of DKA and DKA risk.

inTandem4 Primary and Secondary Efficacy Endpoint Results

Endpoints (placebo-adjusted for all efficacy endpoints)	Sotagliflozin 75 mg (p-value vs. placebo)	Sotagliflozin 200 mg (p-value vs. placebo)	Sotagliflozin 400 mg (p-value vs. placebo)
A1c	-0.25% (p=0.07)	-0.48% (p<0.001)	0.38% (p=0.006)
Urinary glucose excretion (g/day)	42 (p=0.006)	58 (p<0.001)	70 (p<0.001)
Change in 2-hour postprandial glucose reduction (mg/dl)	-20 (p=0.27)	-27 (p=0.15)	-49 (p=0.006)
Body weight	-1.3 kg (2.9 lbs; p=0.38)	-2.4 kg (5.3 lbs; p<0.001)	-2.8 kg (6.2 lbs; p<0.001)
Change in fasting plasma glucose (mg/dl)	-9 (p=0.51)	-9 (p=0.48)	-21 (p=0.10)
Change in systolic blood pressure (mmHg) in subgroup of patients with baseline ≥130 mmHg	-8.4 (p=0.26)	-6.8 (p=0.28)	-14.3 (p=0.013)

inTandem4 Safety Results

	Sotagliflozin 75 mg	Sotagliflozin 200 mg	Sotagliflozin 400 mg	Placebo
Proportion of patients with ≥1 treatment-emergent adverse events	48.6%	28.6%	34.3%	50%
Number of patients with diarrhea	0	1	1	0
Number with genital mycotic infection	1	1	1	0
Number with DKA	0	0	1 (2.9%)	0
Number with severe hypoglycemia	1 (2.9%)	1 (2.9%)	1 (2.9%)	0

Efficacy and Safety of Liraglutide in Insulin-Pump-Treated People with Type 1 Diabetes: The Lira Pump Trial

Thomas Dejgaard, MD, PhD, Kirsten Nørgaard, MD, and Christian Frandsen, MD, PhD (Copenhagen University Hospital, Hvidovre, Denmark)

A team of researchers from Copenhagen University Hospital (Hvidovre, Denmark) presented the results of the highly-anticipated Lira Pump Trial demonstrating the clinical potential of the GLP-1 agonist liraglutide as an addition to insulin pump treatment in people with type 1 diabetes. People with type 1 diabetes using CSII and with overweight (n=44) were randomized to receive liraglutide 1.8 mg or placebo in addition to regular insulin pump therapy for 26 weeks. Dr. Thomas Dejgaard outlined the positive primary outcomes: compared to placebo, liraglutide as an add-on to insulin pump treatment produced significant improvements in A1c (-0.6% vs. +0.2%; p<0.001) and weight loss (-7.3 kg [16.1 lbs] vs. -0.6 kg [1.3 lbs]; p<0.001) without increasing the time spent in hypoglycemia (3.2 vs. 3.5 events; p=0.77). While the A1c reduction could be characterized as modest for a GLP-1 agonist, we’re especially impressed by the reduction from a presumably low baseline A1c combined with the substantial weight loss. As expected for a GLP-1 agonist, nausea was the most commonly reported adverse event for participants randomized to the liraglutide treatment arm; 64% of participants experienced this, though it was transient and disappeared over the first few weeks of the study (we’d love to better understand the experience and intensity of nausea since this percentage isn’t that helpful overall). Currently approved for type 2 diabetes (under the trade name Victoza) and obesity (under the trade name Saxenda), these results underscore the potential of liraglutide for type 1 diabetes as well.

• Dr. Kirsten Nørgaard followed with a deeper dive into the impact of add-on liraglutide to insulin dosing and time-in-range. Excitingly, liraglutide as an add-on to insulin pump therapy gave participants significantly more time spent in the normoglycemic range (57% vs. 45%) – a crucial outcome for patient quality of life and perceived therapeutic and personal success. That said, there was no statistically significant difference in time spent in hypoglycemia (defined as <3.9 mmol/l [70 mg/dl]). Very surprisingly (shockingly), liraglutide also produced no change in total daily dose of insulin; it is less surprising that the distribution between basal and bolus insulin also wasn’t changed.
• Dr. Christian Frandsen closed with a closer look at the effect of liraglutide on weight loss. In addition to producing significant reductions in the primary outcome of body weight, liraglutide also produced reductions in a number of more specific measures of body composition, including total fat, android fat, gynoid fat, and total lean mass. The mechanism of this effect is unclear but likely is not related to food preferences. As revealed by food preference surveys given throughout the study, liraglutide did not appreciably impact food preferences.

Questions and Answers

Q: Your group has already presented nice studies in obese and non-obese people with type 1 diabetes on MDI. What is different about this CSII population that the outcomes are so much better?

A: The A1c reduction in liraglutide treated patients were exactly the same (0.6%) between these trials. The major difference is that here we didn’t see an appreciable A1c change in the patients in the placebo arm, whereas we saw a -0.4% A1c reduction in the placebo arm in the other studies, leaving no significant difference between the treatment and control groups.

Q: Why the choice of a 1.8 mg dose of liraglutide? You showed very impressive weight loss – is this because people with type 1 are more sensitive to the drug? Did any participants need a reduction in dose?

A: I don’t think it’s true that people with type 1 diabetes are more sensitive to liraglutide. A few patients had to reduce to a 1.2 mg dose to minimize nausea side effects.

Q: Do you think these improvements you’re seeing are due to weight loss?

A: A large part of it could be the weight loss, that’s possible.

Oral Presentations: ADA Presidents Oral Session

REMD-477, a Human Glucagon Receptor (GCGR) Antibody, Reduces Daily Insulin Requirements and Improves Glycemic Control in People with Type 1 Diabetes (T1D)

Jeremy Pettus, MD (UCSD, San Diego, CA)

Dr. Jeremy Pettus presented exciting phase 1 data demonstrating that a single dose of the human glucagon receptor (GCGR) antibody REMD-477 can produce substantial and long-lasting (weeks!) reductions in insulin requirements and improvements in glycemia and time-in-range in people with type 1 diabetes, without increasing hypoglycemia. In a double-blind study, people with type 1 diabetes (n=21) were randomized to receive a single subcutaneous injection of either 70 mg REMD-477 or placebo. One day following the injection, participants who received REMD-477 experienced a significant 21% reduction (9 units) in daily insulin dose compared to those who received placebo (p=0.02); this intensified to a 26% reduction (12 units) by the second day after the injection (p=0.02).  Furthermore, REMD-477 produced substantial reductions in average daily blood glucose concentration not days but weeks after the injection. For people in the treatment arm, average glucose fell 27 mg/dl in the first week post-injection (p<0.0010), -31 mg/dl in the second week (p=0.05), and -20 mg/dl in the third week (p=0.05). REMD-477 further produced substantial increases in time-in-range. In the week following the injection, participants on REMD-477 spent 71% of their time in normoglycemia (70-180 mg/dl), versus 56% for those on placebo (p=0.0001), and the effect persisted into the second week post-injection (70% time-in-range with REMD-477, versus 57%; p<0.05). This increased time spent in normoglycemia with REMD-477 was driven by reductions in hyperglycemia; importantly, hypoglycemia did not increase with REMD-477. Although the mechanism of action of this candidate is not yet understood, Dr. Pettus presented evidence that a single dose of REMD-477 produces long lasting elevations in plasma glucagon and GLP-1 that don’t return to baseline until 57 post-injection. Adverse events were infrequent and minor (headache, oropharyngeal pain, etc.) and did not substantially differ between the REMT-477 and placebo groups (11 vs. 10 events), indicating a good safety profile for this candidate. We are very moved by the sheer timescale of REMD-477’s powerful actions and eager to learn more about the upcoming phase 2 study, which according to Dr. Pettus will examine the effect of multiple weekly doses of the peptide drug. For good reason Dr. Pettus’ presentation was certainly one of the most highly-anticipated highlights of the President’s Oral Sessions – the very final event of ADA, highlighting particularly notable late-breaking abstracts – and we will be watching the progress of this work very closely. Although this work is clearly in its earliest stages, REMD-477 is a perfect exemplification of a patient-friendly diabetes therapy that optimizes important outcomes beyond A1c – namely time-in-range and a vastly reduced injection burden.

Oral Presentations: New Insights into Prevention and Treatment of Hypoglycemia

Nasal Glucagon for the Treatment of Moderate-to-Severe Hypoglycemic Episodes in Real-World Settings in Adults with Type 1 Diabetes

Elizabeth Seaquist, MD (University of Minnesota, Minneapolis, MN)

Dr. Elizabeth Seaquist presented positive real-world data on Lilly’s phase 3 nasal glucagon, showing that 96% of patients experiencing hypoglycemia recovered within 30 minutes following treatment and that most of the caregivers were highly satisfied with the device. The study enrolled 129 adults with type 1 diabetes, and 69 of these participants experienced a total of 157 symptomatic moderate or severe hypoglycemia events (a blood glucose of approximately <60 mg/dl or requiring assistance) during the course of the study. For 151 of these episodes (96%), a 3 mg dose of nasally-delivered glucagon met its primary endpoint of “awakening or returning to normal status” within 30 minutes, as determined by a caregiver. For five of the remaining six events, caregivers noted recovery within 45 minutes, and in four of these instances, the patient’s blood glucose was ≥70 mg/dl 30 minutes after administering nasal glucagon. These are impressive results in a real-world setting, confirming what Locemia showed in phase 3 RCTs (Lilly acquired this pipeline product from Locemia in October 2015). A majority of caregivers, 70%, were able to deliver nasal glucagon to a patient experiencing hypoglycemia within 30 seconds, while 98% were able to do so in <2 minutes – what an exciting and much-needed improvement to the lengthy reconstitution process of existing glucagon options. Overall, 94% of caregivers were satisfied with nasal glucagon, including 56% giving it the highest “very satisfied” score. Dr. Seaquist emphasized that no calls to emergency services were made for any of the 157 hypoglycemia episodes, not even for 12 cases of severe hypoglycemia when patients were unconscious or experiencing convulsions or mental disorientation. Impressively, nasal glucagon met the study’s primary endpoint of recovery within 30 minutes in all 12 of these cases as well (experienced by seven participants), which supports the agent’s ability to rapidly raise dangerously low blood glucose in real-world settings. Though an FDA submission has taken longer than we expected since Lilly acquired the phase 3 product from Locemia (due to additional development work and establishing a manufacturing infrastructure), management shared in a separate interview with us that a filing is expected in 1H18, and the product will be submitted in other geographies shortly thereafter. The health and healtheconomic burden of hypoglycemia remains far too high, and we’re hopeful that advances like Lilly’s nasal glucagon will bring us leaps and bounds ahead in our ability to treat the complication. To that end, it’s extremely valuable to see real-world efficacy and feasibility data, since the immediate goal is to help patients/caregivers address hypoglycemia swiftly in everyday settings, avoiding an expensive hospital visit, emergency call, or need for a healthcare professional.

• During a separate call with Dr. Seaquist and Lilly’s nasal glucagon team, we heard anecdotal evidence on caregiver responses to this innovative product: “it just makes so much sense to them.” Certainly, this intuitive ease of use is crucial for a product like glucagon, used often in high-stress emergency situations. Once nasal glucagon is available, we’ll be fascinated to see how the ease-of-use and satisfaction compares to upcoming auto-injectors in development (Xeris and Zealand, among others). 
• According to Lilly management, the shelf life of this innovative product is anticipated to be comparable to current recombinant glucagon. We were happy to hear this, as it will be another pull for patients, providers, and payers. Cost is of course a big question with glucagon, and we so hope that this nasal glucagon is priced responsibly to maximize access to a superior, patient-friendly, cost-saving therapy. 
• Locemia presented equally positive simulated usability data at EASD 2015, which also highlighted the simplicity of nasal delivery.

Effect of Ethanol Intoxication on the Antihypoglycemic Action of Glucagon

Laya Ekhlaspour, MD (Massachussets General Hospital, Boston, MA)

Dr. Laya Ekhlaspour, who at last year’s ADA discussed the merits of a bihormonal bionicpPancreas, now delves deeper into the practicality of micro-dosing with glucagon, presenting findings strongly suggesting that ethanol intoxication does not affect glucagon activity. In a random order crossover trial (n=15) using simultaneous hyperinsulinemic-normoglycemic and ethanol clamps, volunteers with type 1 diabetes were given two identical 50g injections of glucagon while sober and while intoxicated with a blood alcohol content of 0.1%, achieved by delivering the equivalent of 4 drinks in 20 minutes (we bet there are some pretty good stories!). Blood glucose rose following glucagon injection and then stabilized at 90 mg/dl for the duration of the study. Trends were similar in both arms of the study, indicating that ethanol intoxication does not alter glucagon activity and that micro-dosing with glucagon to reverse hypoglycemia is still a safe and effective option when a individual is intoxicated. However, Dr. Ekhlaspour did concede that liver glycogen levels were not recorded during the study, which, as one audience member pointed out, most likely contributed to the observed effect.  In the case of people with alcoholism (who are likely to be poorly nourished), reduced glycogen stores may limit the efficacy of glucagon to lower blood sugar. It should also be noted that with glucagon comes a huge additional cost and burden. Still, we take these results to be an encouraging step in the right direction regarding the pragmatism of a bihormonal bionic pancreas for everyday use.

Posters

Dasiglucagon, a Novel Soluble Glucagon Analog, Successfully Restores Blood Glucose Levels after Hypoglycemia in People with Type 1 Diabetes Mellitus (T1DM) (389-P)

T Heise, B Bysted, U Mouritzen, U Hovelmann, D Lamers, and D Moller

Zealand presented a poster detailing phase 2 results from a PK/PD study of its liquid-stable glucagon analog dasiglucagon. The trial compared four doses of dasiglucagon (0.1 mg, 0.3 mg, 0.6 mg, and 1.0 mg) to native glucagon (Novo Nordisk’s GlucaGen; 0.5 mg and 1.0 mg) in participants with type 1 diabetes (n=58), demonstrating that dasiglucagon, like native glucagon, was able to rapidly and effectively increase blood glucose concentration following a controlled, insulin-induced hypoglycemia event in which blood glucose fell to 55 mg/dl. On the pharmacodynamic front, the three highest dasiglucagon doses (0.3 mg, 0.6 mg, and 1.0 mg) each took a median of six minutes to raise plasma glucose levels to above 70 mg/dl, versus 6 and 7 minutes for the 0.5 mg and 1.0 mg doses of native glucagon, respectively (and 10 minutes for the 0.1 mg dasiglucagon dose). Dasiglucagon furthermore showed comparable performance to native glucagon in terms of the average time required to increase plasma glucose levels by 20 mg/dl; the four dasiglucagon doses (0.1 mg, 0.3 mg, 0.6 mg, and 1.0 mg) respectively took a median of 14, 10, 9, and 9 minutes to achieve this level of plasma glucose reduction, versus 10 minutes for both the 0.5 mg and 1.0 mg native glucagon doses. Notably, the increase in plasma glucose was longer-lasting and more pronounced with dasiglucagon: total plasma glucose excursions (as measured by area under the effect curve [AUE]) were significantly higher with 0.3 mg dasiglucagon versus 0.5 mg native glucagon (p<0.0001) and for both 0.6 mg (p=0.0043) and 1 mg (p<0.0001) dasiglucagon versus 1.0 mg native glucagon. This larger glucose excursion profile promisingly suggests that dasiglucagon may be superior to native glucagon at preventing recurrent hypoglycemia. On the pharmacokinetic front, dasiglucagon reached maximum exposure significantly later than native glucagon (~35 minutes; p<0.01), but demonstrated a significantly higher total exposure for all dose comparisons (p<0.001). In a separate conversation with Zealand, the company indicated that this could be suggestive of higher viability for dasiglucagon over native glucagon, meaning that dasiglucagon could achieve the same the same glucose increasing efficacy at lower doses – but of course this would need to be verified in future studies. Importantly, dasiglucagon was well-tolerated with a similar safety profile as native glucagon. For both dasiglucagon and native glucagon, the most commonly reported adverse events were nausea and vomiting (40 events with dasiglucagon, 35 events with native glucagon) and mild injection site reactions which disappeared within 30 minutes post-dosing (7 events with dasiglucagon, 5 events with native glucagon).

• Following the release of these topline results in 3Q16, Zealand commented in its 4Q16 earnings update that the FDA is expected to provide guidance of dasiglucagon’s development in 1Q17. The candidate is currently in phase 2 development both as a single-dose rescue pen (phase 3 to begin as soon as 3Q17) and as a multi-dose component of a dual hormone artificial pancreas system. We are very pleased to see this progress toward a more patient-friendly and feasible alternative to the current very complex, error-prone native glucagon kits – a longstanding area for improvement in diabetes care. For more on the soluble glucagon arena more broadly, check out our soluble glucagon competitive landscape.

Mini-Dose Glucagon as a Novel Approach to Prevent Exercise-Induced Hypoglycemia in Type 1 Diabetes (67-LB)

M Rickels, S Dubose, H Wolpert, E Toschi, R Beck, M Cummins, BJ Newswanger, and MC Riddell

This phase 2 study compared Xeris’ G-Pen Mini glucagon vs. basal insulin reduction vs. glucose tabs as a way to avoid exercise-induced hypoglycemia, a persistent problem since the natural glucagon response is impaired in people with type 1 diabetes. Each trial participant (n=15) went through four conditions in a randomized crossover design: (i) control, (ii) 50% basal rate reduction five minutes prior to the start of exercise, (iii) oral glucose tabs (20 grams five minutes before start, and another 20 grams 30 minutes after start), and (iv) Xeris’ mini-dose glucagon injected subcutaneously into the abdomen five minutes prior to the start of exercise. The G-pen injection maintained plasma glucose levels between 125-175 mg/dl throughout the duration of exercise (45 minutes) and for 45 minutes after, while glucose tabs elevated blood sugar >225 mg/dl 45 minutes-post exercise. Basal insulin reduction was significantly less effective in avoiding hypoglycemia (p<0.001 vs. G-Pen), as mean plasma glucose dropped to ~75 mg/dl by the end of exercise and stayed low for 45 minutes after, which parallels almost exactly what happened on average in the control condition. In total, six people experienced hypoglycemia (defined by blood sugar <70 mg/dl) in the control condition, five in the basal rate reduction condition, and none in the mini-dose glucagon or oral tabs conditions. On the opposite end, five individuals experienced hyperglycemia (defined by blood sugar >250 mg/dl) in the oral tabs condition vs. only one in the mini-dose glucagon condition and none in the control or basal rate reduction conditions. These results show promising early efficacy for Xeris’ G-Pen Mini as a solution for exercise-induced hypoglycemia in type 1 diabetes – compared to control, basal insulin reduction, and oral glucose tabs, this mini-dose of glucagon minimized both hypoglycemia and hyperglycemia during and immediately after exercise. This study is particularly important since it also  shows how much more effective a small dose of glucagon is if given just before exercise, rather than waiting until hypoglycemia develops during exercise, the latter of which is repeatedly observed in duel hormone studies using glucagon in artificial pancreas  studies. The poster concludes that this phase 2 data supports a larger, longer-term study of Xeris’ G-Pen Mini, which we’d love to see. Xeris currently has one of the most advanced clinical programs for glucagon, and we’ll be watching eagerly for updates. See our glucagon competitive landscape for more information.

Efficacy and Safety of Mini-Dose Glucagon for Treatment of Nonsevere Hypoglycemia in Adults with Type 1 Diabetes (1068-P)

MW Haymond, S Dubose, MR Rickels, H Wolpert, VN Shah, JL Sherr, RS Weinstock, S Agarwal, AS Verdejo, MJ Cummins, B Newswanger, and RW Beck

Xeris’ G-Pen Mini was investigated in 17 adults with type 1 diabetes as a treatment for nonsevere hypoglycemia. In a randomized crossover design, participants spent three weeks with mini-dose glucagon and three weeks with oral glucose tabs to treat any cases of mild hypoglycemia. The primary endpoint of “success” was defined as blood glucose ≥50 mg/dl 15 minutes following treatment and blood glucose ≥70 mg/dl 30 minutes following treatment – 94% of patients in the mini-dose glucagon arm achieved success vs. 95% of patients in the glucose tabs arm. BGM and CGM data showed a similar profile for the G-Pen Mini vs. oral glucose tabs. In the first hour post-hypoglycemic event, people in the glucagon group spent 62% of time-in-range vs. 67% for people in the glucose tabs group (p=0.86). In the first two hours post-hypoglycemic event, participants in both groups spent a mean 79% of time-in-range (p=0.49). Time <70 mg/dl was a mean 35% for the glucagon group one hour post-hypoglycemia vs. 33% for the glucose tabs group (p=0.95). Two hours post-hypoglycemia, these values were 20% and 19%, respectively (p=0.63). The non-significant p-values indicate the G-Pen Mini’s non-inferiority vs. oral glucose tabs as a treatment for mild hypoglycemia, but the poster points out other distinct advantages to mini-dose glucagon: Namely, carbohydrates as a solution to nonsevere hypoglycemia lead to excess caloric intake and excess hyperglycemia, all of which could be avoided with Xeris’ G-Pen Mini. After six weeks of the study, participants were asked to choose between the two treatment options for an additional three weeks – ~50% opted to continue mini-dose glucagon. Injection discomfort and nausea were the primary reported adverse events associated with the G-Pen Mini, affecting 15 and three participants, respectively. Overall, these results support continued investigation of Xeris’ product for mild-to-moderate hypoglycemia, and we look forward to future data readouts. Xeris is an industry leader right now in the glucagon competitive landscape, and we’re very happy to see forward progress on the company’s various glucagon candidates.

Symposium: Preserving the Beta Cell Function

How Do We Protect the Beta Cell in Type 1 Diabetes?

Aaron Michels, MD (University of Colorado, Aurora, CO)

Dr. Aaron Michels from the University of Colorado Denver School of Medicine characterized type 1 diabetes as an immune-mediated disorder with beta cells actively contributing to disease pathogenesis. He discussed the stages of disease development, explaining that as of 2017, we are able to predict type 1 diabetes but we can’t effectively prevent it. Knowing what to target and monitor with immune therapies is critical. The study of human islet infiltrating immune cells provides disease-specific targets for immune therapies and suggests potential biomarkers for disease activity. Elucidating the immune-beta cell interface will help researchers devise strategies to protect beta cells. Dr. Michels highlighted that lobular beta cell destruction in the human pancreas, beta cells overexpressing HLA Class I, and blocked immune checkpoint inhibitors are all possible contenders leading to type 1 diabetes. The natural history of type 1 diabetes involves genetic risk, environmental triggers, beta cell injury, prediabetes, and diabetes. Attempts at beta cell preservation in people with type 1 diabetes have been minimally effective so far, but we are excited to continue following this important field.

Assessing Beta-Cell Function

Jerry Palmer, MD (VA Puget Sound Healthcare System, Seattle, WA)

Dr. Jerry Palmer reviewed multiple methods of assessing beta cell function in people with diabetes, or in those with prediabetes or presymptomatic type 1 diabetes. In this presentation, Dr. Palmer drew on data from both patients with type 1 and type 2 diabetes. He reviewed several different methods of assessing beta cell function, including measuring insulin secretion (particularly the amount and timing) and assessing proinsulin processing. He also acknowledged the statistical issues associated with measuring beta cell function. He closed by highlighting the Restoring Insulin Secretion (RISE) trial. While noting that it is still too early to draw conclusions from the trial, Dr. Palmer shared that the protocol of measuring beta cell function in the trial (via hyperglycemic clamps and oral glucose tolerance tests) is functioning well, based on the first few years of recruitment and early follow-up.

• The delayed release of the C-peptide in response to oral insulin is an early indicator of risk for diabetes. The progression to diabetes is generally characterized by rising glucose levels accompanied by normal C-peptide levels at fasting glucose until about six months before the diagnosis. However, Dr. Palmer pointed to a study led by Jay Sosenko in the DPT-1 trial showed that when abnormalities in C-peptide response to oral glucose are measured, there is a delay in the response of those progressing toward a diagnosis compared to those who are not going at least as far back as 2 years (p<.01). 
• Mixed meal tests (MMT) were found to be more reproducible and better tolerated than glucagon stimulation tests in two trials. When addressing the issues of statistical sensitivity, specific and reproducibility in assessing patients’ beta cell function, Dr. Palmer noted that both the TrialNet Study (n-148) and a European C-Peptide Trial (N=118) had conducted both these tests on the same recently-diagnosed patients and repeated them with in 3-10 days. There results showed that the MMT was more reproducible, better tolerated by patients with fewer adverse effects, and preferred. He stated the MMT was a stronger test and more sensitive to residual insulin secretion.

Questions and Answers

Q: If you had to choose which of the tests you demonstrated was the most highly sensitive for people, which would you use?

A: Firstly, it’s pretty well established that prior to diagnosis of type 1 we do glucose tolerance and then after do a mixed meal tolerance. I think what we need to do is model those two tests, maybe add some additional data points, such that we can get a measure of insulin sensitivity, so that whenever we talk about insulin secretion we do it in the context of how insulin sensitive patients are rather than absolute numbers.

Symposium: Technical Innovations in Islet Transplantation—Novel Approaches

Engineering Novel Encapsulation Platforms for Islets

Cherie Stabler, PhD (University of Florida, Gainesville, FL)

Dr. Cherie Stabler highlighted several novel beta cell encapsulation approaches that she views as particularly promising, including microencapsulation, nanoscale coatings, and new coatings created by covalent layer-by-layer encapsulation. She emphasized how these efforts can address several key considerations in the effort to fabricate nano-scale barriers to encapsulate pancreatic islets, such as ensuring a controllable thickness (through nanoscale control of capsule) and long-term mechanical stability (through covalently linking layers). According to Dr. Stabler, a “home run”  in encapsulation would involve resolving the immunological problem, the cell source problem, and the transplant problem. Islet encapsulation must solve issues of permeability, biocompatibility, and stability as well. The material must be permeable enough to allow nutrients such as glucose and oxygen to come into the islet and for insulin to leave the islet, while also being non-permeable to antibodies. Many materials degrade when put into the body, so the material must be stable enough to survive. In conventional microencapsulation, islets suffer from poor delivery of oxygen and nutrients, sluggish glucose response and insulin secretion, exacerbated by transplant site. ViaCyte has experienced some of these challenges firsthand in its phase 1/2 trial of PEC-Encap – due to the challenges with fibrosis and variable patient responses, the company has de-prioritized this effort to some extent and is instead focused on PEC-Direct, a direct vasculaization product that does not protect ViaCyte’s stem cell-derived islet progenitor cells from the immune system (requiring patients to take immunosuppressants. We’re so very glad that very smart people like Dr. Stabler are hard at work at creating next-generation encapsulation devices that can hopefully avoid some of the pitfalls of the first-generation efforts.

Bioengineering the Transplant Site―Application to Clinical Therapy

James Shapiro, MD, PhD (University of Alberta, Edmonton, Canada)

Dr. James Shapiro provided an overview of the current research to improve islet cell transplantation, concluding that bioengineering transplants is effective and that latest therapeutic cells are promising. He noted up front that while cadaveric islet cell transplantation via the Edmonton protocol (through the portal vein in the liver) are safe, simple, result in a predictable function of the C-peptide, and are therefore currently unmatched for efficacy. That said, he acknowledged that traditional transplantation through this method is not scalable, as it is not easy to procure donor cells, many cells are lost during the transplant (requiring multiple transfers), there is a risk of bleeding and clot, and retrieval is difficult. He highlighted several novel, alternative strategies, including: (i) bioengineering of the intra-abdominal endocrine pancreas; (ii) gastric submuscal transplantation of islets; (iii) device-less transplants; (iv) transplanted devices; (v) new cell products; (vi) cell product manipulation; and (vii) cell product co-transplantation. Dr. Shapiro concluded by cautioning that that vascularity and oxygen generation will need to improve in transplant sites outside of the portal vein before they become true alternatives, and that the “we may have to take a step back” from current portal efficacy as we improve these sites. ViaCyte in particular has experienced challenged with fibrosis and unpredictable, varied efficacy in its phase 1/2 trial of beta cell encapsulation product PEC-Encap. It’s clear that quite a few questions must be addressed before beta cell replacement and encapsulation become a viable type 1 diabetes cure therapy for the broader population.

• Dr. Shaprio highlighted his research with ViaCyte’s stem cell-derived islet cell replacement therapies PEC-Encap and PEC-Direct , characterizing these efforts as some of the more promising cell therapies. PEC-Encap delivers beta cell progenitors through ViaCyte’s Encaptra device and showed some promise, though it the device was challenged by the body’s foreign body response. He is hopeful PEC-Direct, the new product from ViaCyte which allows for direct vascularization of implanted cells, will have better vascularization results and cell survival, though it will have to be taken with an immunosuppressant. PEC-Direct was recently approved for clinical trials by the FDA and Canada.
• Dr. Shapiro also spoke briefly to new promising research in cell manipulation, specifically caspase inhibitors and apoptosis inhibitors. He expanded on the research he is doing with Conatus Pharmaceuticals into whether emricasan (IDN-6556) helps protect against allo- and autoimmunity of islet cell transplant recipients. Emricasan is also currently being developed by Conatus for NASH, in partnership with Novartis. Dr. Shapiro observed that in vitro manipulation of cells to confer protection can have a profound impact, and he is hopeful about where the research may go.
• He also highlighted recent research in bioengineering the transplant site, citing the recent example of researchers utilizing the intraabdominal endocrine pancreas for a patient. In this case the single patient had 602,395 islet equivalents were combined with autologous plasma laproscopically layered onto the omentum. The patient came off insulin 17 days after her transplant, and continues to have stable glycemic control, though this was a recent procedure so long-term efficacy is not yet known.

Questions and Answers

Q: Very nice work and talk. In terms of bioengineering sites, you presented initial data but in terms of where this going when you move the data forward, any comment in terms of the end point you envision?

A: We move forward very slowly with this. Portal may be new for some but for us it’s established. We don’t want to expose patients to new approaches until we know there’s some promise, it doesn’t make sense to do this on 20 patients until we’ve seen it’s effective in a few. It is a tough balance between having a large base and not a large failure.

Symposium: Joint ADA/ISPAD Symposium—Current Status of Complications in Youth with Type 1 Diabetes

Update on Macrovascular Disease and Risk Factors—Time to be More Aggressive with Treatment?

David Maahs, MD (Stanford Children’s Health, Palo Alto, CA)

Cardiovascular disease (CVD) and the associated risk in patients with diabetes is an increasingly important topic and Dr. David Maahs made it clear that vigilance and aggressive steps are needed to rectify this association even in younger patients with diabetes. Dr. Maahs noted that although aggressive A1c control does not eliminate CV risk he would still like to see current progress on lowering A1c levels “move more quickly” as only 30% of pediatric patients are meeting A1c goals.  Citing data from the T1D Exchange that 69% of patients ages 6-13 and 62% of patients age 12-30 are not meeting LDL goals, Dr. Maahs reiterated that “we can do better” on cardiovascular outcomes in pediatric patients.  He contextualized this problem by stating that only 1% of pediatric patients is on lipid-lowering medication, giving us a sobering look at how urgent this problem could be in pediatric patients. Dr. Maahs did offer hope that artificial pancreas innovation would allow for better control of A1c levels and cited the SEARCH study that found that for every 1% change in A1c, there was a 4 mg/dl change in LDL levels. Dr. Maahs concluded with a look toward clinical trial data from a study with subjects taking atorvastatin for 6 months showing overall lower lipid levels and a “less atherogenic” cardiovascular profile. The AdDIT Study similarly showed that statins correct lipid abnormalities and show no adverse events. Dr. Maahs summarized by calling for improved screening, better treatment of risk factors to address CVD risk in adulthood, and more longitudinal studies of cardiovascular risk in pediatric patients.

Update on Retinopathy—Should We Screen or Not?

Kim Donoghue, MD (University of Sydney, Australia)

As part of a broader discussion on adolescent and youth complications in type 1 diabetes, Dr. Kim Donoghue provided a summary of the current, varied screening recommendations for diabetic retinopathy,  underscoring the need for quick diagnosis and subsequent intense treatment and metabolic control. Dr. Donoghue reviewed data from a number of studies that showed low to no prevalence of diabetic retinopathy in adolescents and contrasted this with a number of studies that did find higher rates. In a study conducted in the UK, Dr. Donoghue pointed out that 20% of individuals diagnosed with type 1 diabetes before age 2 had developped retinopathy by ages 12-13. This same study found that 9% of children with diabetes diagnosed at under 4 years of age had developed sight-threatening diabetic retinopathy by age 17-18. This was in contrast to studies done by the T1D Exchange, the University of Pennsylvania, and Yale University, which all found zero or very few pediatric patients with diabetic retinopathy. Dr. Donoghue attempted to explain this disconnect, pointing out that the investigations which found no prevalence of retinopathy featured larger proportions of younger adolescents, tracked subjects for shorter periods of time, and used tools that were not powerful to adequately detect retinopathy. Furthermore, recent data demonstrates higher hazard ratios for diabetic retinopathy patients with a longer duration of diabetes (1.6, 1.9, and 1.0 for diagnosis under age 4, between age 5-14, and age 15 or over, respectively). Taken together, these findings suggest that adolescents are at greater risk for diabetic retinopathy than we realize – especially if they have a long diabetes duration. Dr. Donoghue concluded by questioning whether our current recommendations for diabetic retinopathy screening are rigorous enough, asking what prevalence rate of diabetic retinopathy are we willing to accept and calling for increased research into the frequency of diabetic retinoapthy in children, using study cohorts that match the general population.

Symposium: Therapies to Preserve Beta Cells in Type 1 Diabetes (Supported by a grant from The Leona M. and Harry B. Helmsley Charitable Trust)

Therapy for Type 1 Diabetes – Short Treatment for Durable Benefit

Gerald Nepom, MD, PhD (Benaroya Research Institute, Seattle, WA)

Dr. Gerald Nepon discussed the potential role of short treatments with durable benefits in type 1 diabetes intervention. Overall, he noted that immunotherapies often have short-term efficacy, but lack durable and lasting outcomes. Previous therapies have been able to improve C-peptide outcomes temporarily for up to 18 months. However, cells will shortly resume decay after this time period at the original rate, resulting in a recurrence of disease. This transient effect of therapies on preserving beta-cell function is one of the largest challenges in creating therapy for type 1 diabetes. As a result, it may be beneficial to use a combination of therapeutic strategies that target T-cell memory. As an example of this, Dr. Nepom reviewed the findings from the phase 2 T1DAL study of anti-CD2 therapy alefacept, a drug that depletes effector memory lymphocytes. One-year and two-year results (presented at ADA 2013 and ADA 2015, respectively) observed that individuals taking alefacept experienced lower rates of hypoglycemiaduring and after the study, suggesting that the drug leads to durable effects and outcomes. That said, the study failed its primary endpoint of change in C-peptide AUC. Dr. Nepom concluded by emphasizing the importance of using multiple mechanism-informed strategies when creating therapeutic interventions. He further suggested that combination immunotherapy targeting T-cell memory is especially promising, due to T-cells’ ability to induce and stabilize remission and create transcriptional markers that stabilize phenotypes.

Questions and Answers

Q: Why did the incidence of hypoglycemic incidence decline?

A: The incidence of hypoglycemic incidence declined because the therapy cleared islet inflammation and allowed counter-inflammation to happen regularly.

Disease-Specific Therapy (Antigen-Specific Immunotherapy)

Carolin Daniel, PhD (Helmholtz Zentrum München, Munich, Germany)

Dr. Carolin Daniel began her talk by emphasizing the importance of immune tolerance restoration in type 1 diabetes. She presented an overview of an experiment that used humanized mice to see if regulatory FoxP3 T-cells (Tregs) could be generated in vivo. From the Tregs generated in humanized mice, methylation analyses of Foxp3 Treg-specific demethylated regions showed that the induced human Tregs from humanized mice were stable, functional, and prevented the development of type 1 diabetes. The implications of this finding are especially important for childhood type 1 diabetes, as higher frequencies of insulin Tregs may be linked to slower progression of the condition. Furthermore, there may be evidence suggesting that for children with islet autoimmunity, insulin-specific Treg cells may play an important role in the progression of type 1 diabetes. Dr. Daniel concluded by emphasizing the importance of future studies that increase our mechanistic understanding identified impairments in Treg induction and that better model islet autoimmunity in humanized mice.

• Dr. Daniel described the process of in vivo human Treg induction in humanized mice. Tregs are induced in the mice through Greg conversion and subimmunogenic antigen stimulation. Greg conversion activated T-cells through agonist ligands, and human Tregs are induced through subimmunogenic stimulation. CD34+ cells are also developed, which are used to identify the incidence-specific T-cells. Induced Tregs are then observed and functionally characterized to test the mRNA abundance of Greg signature genes and T-cell effector genes. Analysis of the induced human Tregs indicated that higher frequencies of Tregs may be associated with slower onset of type 1 diabetes. 

Symposium: Bariatric Surgery in Special Populations

Bariatric Surgery in Type 1 Diabetes

Sangeeta Kashyap, MD (Cleveland Clinic, Cleveland, OH)

Dr. Sangeeta Kashyap presented data on the use of bariatric surgery in type 1 diabetes, concluding that surgery can lead to substantial weight loss and improved glycemic control in severely obese people with type 1 diabetes. Dr. Kashyap first presented a case series (n=10) of type 1 diabetes patients (mean baseline BMI of 42 kg/m²; mean diabetes duration of 22 years), with results showing that at a mean follow up of 36 months, “excess weight loss >60%” was achieved in all patients except in one case of adjustable gastric banding. In addition, mean A1c levels dropped by 1.1% (baseline of 10%, p=0.039) and insulin requirements dropped by 0.34 U/kg/day (baseline of 0.74 U/kg/day, p=0.004). Next, Dr. Kashyap presented results of a meta-analysis of 16 studies (n=106) published between 2013 and 2015, which similarly demonstrated significant BMI reductions (41.9 to 31 kg/m²), reduced insulin requirements, as well as reduced use of anti-hypertensive and lipid lowering agents. Notably, she stated that this patient population tended to experience profound glycemic changes (DKA, severe hypoglycemia) and GI dysmotility symptoms (prolonged ileus, acute gastric remnant dilation) in addition to the common postoperative complications of bariatric surgery. However, in conclusion, Dr. Kashyap noted that the favorable metabolic effects of bariatric surgery may facilitate medical management of type 1 diabetes in the setting of severe obesity.

Questions and Answers

Q: Our experience with surgery in type 1 diabetes has not been positive. We’ve seen huge swings in glycemic control.

A: For the long term, these are difficult patients to manage. But even prior to surgery, it’s also difficult to control. I have patients on U500 drips and they’re really poorly controlled. There are going to be a few patients that will require something like this.

Q: I had a patient who had type 1 diabetes and RYGB and she suffered from severe hypoglycemia. What’s your experience with hypo?

A: We’ve had similar experiences. We’ve had to work very closely with nutritionists to tell them to eat more frequently, to use rapidly acting insulin, and to use insulin pumps. These are all things we need to individualize. The data for patients who had sleeve is far more encouraging. We don’t see those huge fluctuations with sleeve patients. Also our banded patients have been far easier to manage in terms of glucose excursions.

Symposium: Beta Cells Under Attack—Lessons from Transplantation for New-Onset Type 1 Diabetes

Addressing Cellular Immunity―Transplant Therapies Applied to New-Onset Type 1 Diabetes

Antoinette Moran, MD (University of Minnesota, Minneapolis, MN)

Dr. Antoinette Moran discussed lessons learned from transplant therapy immunosuppression that can be applied to treating new-onset type 1 diabetes. She underscored that manipulation of cellular immunity is key to preventing transplanted organ rejection. What’s more, alloimmune and autoimmune activation follow similar pathways and can be similarly blocked. Drugs that act at multiple points in the cellular activation pathway can also be used in type 1 diabetes, and combining multiple drugs is always required to prevent transplant allograft rejection – there is similar growing consensus in the diabetes that combination immune therapy will very likely be required for type 1 daibetes. In addition, two phases of immune therapy are generally required in transplant— an intensive induction phase followed by a less suppressive maintenance phase which is life-long. No therapy is one size fit all, as there is clinical heterogeneity in both disease manifestations and the response to immunotherapy. As a result, she emphasized that individual approaches likely need to be developed. In addition, she noted that children have a different disease course and response to immunotherapy compared to adults, including differences in pharmacokinetics of immunosuppressive drugs, length of exposure to immunosuppression, and possible interference with vaccinations. Children are also uniquely susceptible to toxicities related to growth, development, and cognitive function – thus it’s imperative that they are studied and considered separately from adults. We are excited that progress in immunosuppression therapy over the last 30 years has allowed long term success in organ transplantation and we’re pleased that some of the lessions from this experiment can be applied to the treatment of autoimmune conditions like type 1 diabetes.

Protecting the Beta Cell from Innate Immunity

Lorenzo Piemonti, MD (San Raffaele Scientific Institute, Milan, Italy)

Instead of the traditional beta cell transplantation strategy of increasing the potency of generalized immunosuppression regimes, Dr. Lorenzo Piemonti hopes to develop novel clinical protocols based on the use of drugs that more specifically target the immune response against transplanted beta cells. According to Dr. Piemonti, immediately after islet infusion, as much as 50% of the transplanted beta cells are lost in less than 24 hours thanks to the detrimental impact of the non-specific immune response and pre-existing and transplant-induced specific cellular immune responses against the beta cells. Dr. Piemonti’s work therefore focuses on identifying “master regulators” of the immune response and using techniques such as CXCR1/2 blockade and CCL2 blockade to quell inflammation. We certainly look forward to hearing how this work progresses; circumventing the immune response has remained the foremost challenge in beta cell transplantation work.

Beta-Cell Biomarkers―Assessing Islet Loss in Transplant and Type 1 Diabetes

Kevan Herold, MD (Yale University, New Haven, CT)

Dr. Kevan Herold gave a fascinating talk on the development of an assay to assess beta cell death and to better understand the natural history of beta cell loss. Beta cell death is a silent event and the timing and precipitants of it are largely unknown. Measuring beta cell function is one approach, but it can be affected by other environmental factors and thus inaccurate. To solve this problem the Herold lab developed an assay that can measure beta cell death through the release of insulin DNA with unmethylated CpG sites into the bloodstream by using droplet digital PCR. The first design of the assay used a nested PCR reaction to detect primers that amplified the CpG sites and then ran rtPCR detecting the difference between methylated and unmethylated sites. In a more sensitive and specific method of ddPCR, the lab can run tens of thousands of reactions in droplets to determine the methylation ratio. With the assay, the Herold lab found that there is high beta cell death and elevated unmethylated insulin DNA after total pancreatectomy with islet autotransplantion in young patients with congenital pancreatitis issues. It also found that much of the material is dead already in allogeneic islet transplantation. Other research groups have started using this technique, and have found a large increase in unmethylated DNA right after a transplant as well as higher levels in type 1 diabetes patients compared to those without diabetes. Another group put human islets into a mouse and looked at human islet cell death after transplant, seeing a huge increase in unmethylated rather than methylated DNA. In a study examining TrialNet Natural History subjects who were “at risk,” “high risk,” or had new onset type 1 diabetes, the “high risk” group had high unmethylated DNA levels, and they were significantly different in progressors, nonprogressors, and normal subgroups. This led to a new model of beta cell loss in type 1 diabetes where beta cell death takes place suddenly, rather than in a slow decline. The researchers also saw biomarker decline when patients were treated with anti-CD3 monoclonal antibody and not when treated with placebo (mirroring C-peptide). However, pitfalls to the assay remain in finding appropriate CpG sites to increase the specificity and sensitivity of the test and better understanding how beta cell stress may prevent methylation because of inflammation, epigenetic changes, and changes in function. Nevertheless, the assay is a valuable method of measuring beta cell killing in vivo, acting as a thermometer for beta cell health, and quantifying the loss of islets after transplantation or through autoimmune processes.

Questions and Answers

Q: There are a lot of different types of beta cell death, and macrophages may have different levels of efficacy in disposing of them. Does the type of death matter? Is there a difference in disposal?

A: That’s an extremely good question and we don’t know. We would need to model it in vitro to see the different types of death. It could be that apoptosis is completely silent in our assay.

Q: In the subpopulation of beta cells that are resistant to immune attack, I understand there is an upregulation of PDL1. Are all the beta cells expressing it?

A: They do increase expression of PDL1 and decrease beta cell antigens and seem to be resistant to killing. We’ve thought about this in checkpoint induced diabetes and we know of three tissues that do that in response to stress (your brain, your heart, and beta cells).

Lessons from Islet Physiology—Plasticity of Islet-Cell Function

Patrick MacDonald, PhD (University of Alberta, Edmonton, Canada)

Islet cell plasticity and heterogeneity has received increased interest in recent years, and while research has delved into cell identity phenotypes, there is still a knowledge gap in functional phenotypes of beta cells. At the Alberta Diabetes Institute IsletCore, Dr. Patrick MacDonald described the program to process organs for islet isolation, banking, and distribution and reviewed islet cell plasticity through the malleability of beta cell function in infants, the exocytotic capacity in beta cell compensation and failure, and function consequences of alpha cell to beta cell transdifferentiation. His presentation first focused on the malleability of beta cell function in infants, where islet isolations from infants expressing PDx1 and other islet markers start to lose these in culture over time and lose their phenotype. The islets did not function well and lost some functional proteins and had metabolic defects. This is not seen in adult islets because infant cells unlike adult cells cannot mount an exocytotic response to stress. When the lab ran infant cells through a ViaCyte like expansion and maturation protocol, they were able to reexpress proteins, demonstrating how the exocytotic response is plastic in infancy and occurs even in cells that retain insulin expression. The exocytotic capacity in beta cell compensation and failure is a functional measure of secretory granule available for release upon stimulation of an islet cell. Glucose exposure upregulates beta cell exocytotic capacity but these responses fail in type 2 diabetes. The loss of this pathway leads to impaired adaptation to a high fat diet in mice and contributes to a functional change to hyperinsulinemia and is dysfunctional in older people. Finally, Dr. MacDonald reviewed the functional consequences of alpha cell to beta cell transdifferentiation and the role of alpha cell dysfunction in diabetes. Functional changes in human type 2 diabetes alpha cells start to mimic exocytosis of beta cells, which can be recapitulated in high fat diet fed mice, including the hypersecretion of glucagon. In mouse models, deleting certain genes in alpha cells make them resemble beta cells in some phenotypes of glucose regulation of exocytosis, which is a fascinating and poorly misunderstood plasticity in “flipped” islet cells.

Symposium: The Future Face of Diabetes Care – Beta-Cell Replacement vs. Technology (Supported by a grant from The Leona M. and Harry B. Helmsley Charitable Trust

The Future of Diabetes Management Is Cell Replacement Therapy

Jeffrey Millman, PhD (Washington University in St. Louis, St. Louis, MO)

Dr. Jeffrey Millman, an alumnus of Harvard’s Dr. Doug Melton’s lab (and now of Washington University in St. Louis), offered a compelling overview of the current state of the stem cell-derived beta cell field, outlining the remaining challenges toward a viable beta cell replacement therapy. Dr. Millman highlighted two main ongoing challenges: (i) cell potency; and (ii) cell delivery. Of the two, he characterized cell potency as a largely solvable problem. He noted that, while current stem cell-derived beta cells are very similar to native, primary beta cells, there are still substantial differences in the expression levels of several important genes – this suggests that the stem cell-produced cells are not completely identical to human beta cells, which may have important functional implications. Notably, for instance, stem cell-derived beta cells have poorer insulin secretion than endogenous human beta cells. Dr. Millman showed data demonstrating the per-cell level of insulin secretion of the very best of stem cell-derived beta cells is comparable to the very worst of isolated human islets. That said, Dr. Millman emphasized that much progress has been made on this front and that the latest cells produced from his lab’s new, revised protocol appears to match the insulin secretion levels of human islets more consistently. On the other hand, Dr. Millman views cell delivery as the much larger limitation currently facing beta cell replacement therapy. As he put it, transplanted cells must be able to survive, which requires that they receive a steady stream of oxygen and nutrients while being protected from autoimmune attack. At the same time, the protection system must still allow for rapid diffusion of glucose to and away from the cells, or else there would be an unacceptable lag in the system, which could produce an unacceptable risk of hypoglycemia. Finally, concerns about the tumorigenic potential of these stem cell-derived products persist as well. Overall, given the novel nature of these cells, Dr. Millman emphasized the importance of being able to retrieve the cells for safety reasons – which rules out the gold standard Edmonton protocol that is currently used to transplant human islets. He highlighted a few of the ongoing efforts in beta cell encapsulation, including his work in collaboration with Dr. Dan Anderson’s lab at MIT to encapsulate cells in an immune-protective alginate device. We heard similar commentary on the limitations of beta cell replacement therapy from Dr. Doug Melton at Levine-Riggs 2017. While these challenges are to be reckoned with for sure, we’re encouraged that these greats don’t view them as insurmountable and we’re eager to see where this field goes in the next couple of years.

Professional Interest Group Session: Staging Presymptomatic Type 1 Diabetes – Is There Enough Evidence? (Supported by the Helmsley Charitable Trust)

Richard Insel, MD (Insel Consulting, New York, NY) and Dorothy Becker, MB (Children’s Hospital of Pittsburgh, PA)

In a “debate” that offered much more agreement than controversy, Drs. Richard Insel and Dorothy Becker provided a perspective on the rationale behind and remaining questions with regards to staging of presymptomatic type 1 diabetes. Dr. Insel emphasized the benefits of staging type 1 diabetes (and screening to identify patients at presymptomatic stages), including the opportunity to identify type 1 diabetes at an earlier time point (reducing the likelihood of diagnosis in DKA), potential to intervene earlier in type 1 diabetes with clinical trials for specific stages, and the chance to generate insights to refine the stages and optimize design of clinical trials for type 1 diabetes. Dr. Becker began her “counterargument” by stating that she’s actually in favor of the concept of staging presymptomatic type 1 diabetes. That said, she acknowledged several ongoing “hang-ups” in the field regarding this. She suggested one of the major issues is semantics – the term of presymptomatic type 1 diabetes has gone through several iterations, from “chemical diabetes” in 1972 to “prediabetes” in the 1980s to “presymptomatic T1D staging” in 2015. She highlighted the most recent term that has gained traction: Autoimmune Beta Cell Disorder (ABCD). She prefers this term to some degree, as it makes clear that type 1 diabetes is a disorder and not a disease (the latter term implies some sort of infection) and she emphasized that the development of autoantibodies is a marker of a potentially severe process, but not should be used to imply pathogenesis. We like the rationale behind this term, though it may be confused with the newly proposed “ABCD” term of obesity. Other potential issues with staging highlighted by Dr. Becker included heterogeneity in the rates of type 1 diabetes progression and the fact that there’s no treatment yet (though she pointed out that, ideally, treatments to delay or prevent type 1 diabetes could be developed for these presymptomatic stages). Overall, Dr. Becker emphasized the importance of refining the current stages of type 1 diabetes and cautioned against “throwing the baby out with the bathwater” by abandoning stages altogether. Hear hear!

Symposium: Biomarkers of Type 1 Diabetes

Biomarkers of Disease Progression and Efficacy/Treatment in Type 1 Diabetes

Massimo Pietropaolo, MD (Baylor College of Medicine, Houston, TX)

Dr. Massimo Pietropaolo highlighted the role of biomarkers in assessing type 1 diabetes progression, as well as the efficacy of potential therapies for type 1 diabetes. In pa